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Robert Trent Jones Golf Trail
The Robert Trent Jones Golf Trail is a collection of championship caliber golf courses, designed by Robert Trent Jones, Sr., distributed across the state of Alabama, as part of investments by the Retirement Systems of Alabama. The Trail started with 378 holes at eight sites throughout the state, but has grown to 468 holes at eleven sites.
The concept was created and executed by David G. Bronner, CEO of the Retirement Systems of Alabama. The mission was to effectively diversify the assets of the state's pension fund and economically help the state of Alabama, the philosophy being that "the stronger the Retirement Systems of Alabama can make Alabama, the stronger the Retirement Systems will be."
LPGA Tour
Two of the courses currently host events on the LPGA Tour: The Senator course at Capitol Hill near Montgomery, which hosts the Yokohama Tire LPGA Classic, and The Crossings course at Magnolia Grove near Mobile, home to the Airbus LPGA Classic.
PGA Tour
The Grand National course in Opelika hosted the first PGA Tour event in Alabama since the 1990 PGA Championship, the 2015 Barbasol Championship.
Courses and locations
Cambrian Ridge (Greenville)
Canyon (9 holes)
Sherling (9 holes)
Loblolly (9 holes)
Short Course (9 holes)
Played as Canyon/Loblolly, Loblolly/Sherling, or Sherling/Canyon.
Capitol Hill (Prattville/Montgomery)
Judge
Legislator
Senator
Grand National (Auburn/Opelika)
Lake
Links
Short Course
Hampton Cove (Huntsville)
Highlands
River
Short Course
Highland Oaks (Dothan)
Highlands (9 holes)
Marshwood (9 holes)
Magnolia (9 holes)
Short Course (9 holes)
Played as Highlands/Marshwood, Magnolia/Highlands, or Marshwood/Magnolia.
Lakewood Golf Club (Point Clear)
Azalea
Dogwood
Magnolia Grove (Mobile)
Crossings
Falls
Short Course
Oxmoor Valley (Birmingham)
Ridge
Valley
Short Course
Ross Bridge (Hoover/Birmingham)
Silver Lakes (Gadsden/Anniston)
Backbreaker (9 holes)
Heartbreaker (9 holes)
Mindbreaker (9 holes)
Short Course (9 holes)
Played as Backbreaker/Mindbreaker, Heartbreaker/Backbreaker, or Mindbreaker/Heartbreaker.
The Shoals (Muscle Shoals/Florence)
Fighting Joe
Schoolmaster
Scorecards
Scorecards for courses played on the PGA and LPGA Tours.
References
External links
Official site
Robert Trent Jones Golf Trail article in the Encyclopedia of Alabama
Category:Golf clubs and courses designed by Robert Trent Jones
Category:Landmarks in Alabama
Category:Golf clubs and courses in Alabama
Category:Sports venues in Alabama |
Detroit Tigers relief pitcher Joe Nathan is congratulated after his save in the ninth inning of a baseball game against the Kansas City Royals in Detroit, Thursday, June 19, 2014. (AP Photo/Carlos Osorio)
Thursday at Comerica Park, it was as if the Tigers had been dropped into a time tunnel.
Not back to long ago. Just April, and the first half of May.
It was like the Tigers were 27-12 again, and skipped the 9-20 span, which sent the club reeling. And as if the unfortunate, “I beat my wife” joke shockingly blurted out by manager Brad Ausmus on Wednesday, never occurred.
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Austin Jackson had an important hit. Miguel Cabrera hit a rocket for an RBI double to score him. Some guy named Martinez – although it was rookie J.D. instead of veteran Victor – hit a home run.
Joe Nathan, the active MLB saves leader and ninth all time, came out of the bullpen painting the corners of the plate with a 94 mph fastball. Not only did Nathan save the game, but he struck out the side in the process. Joba Chamberlain pitched a scoreless eighth inning to set up Nathan.
He came in relief of starter Anibal Sanchez, who was brilliant for seven innings. Did the ominous cloud, which had been following the Tigers, dissipate?
Ausmus apologized, this time more extensively, about his comment, while meeting with the media in his office Thursday morning. He said it had been a long 12 hours after he made a crack, which was anything but wise.
“I didn’t sleep well,” he said.
He didn’t blame anything or anybody – the pressure of the Tigers losing, the mainstream media, social media – for his predicament. Only himself.
“It was the worst day,” Ausmus said of his still brief stint as a manager. “I don’t want to candy coat it.”
The incident compounded an already difficult situation in which the Tigers’ 7-game lead had eroded to the point they fell out of first place in the American League Central for the first time in nearly a calendar year.
How should the good that happened to the Tigers Thursday be ranked in importance?
Nathan’s performance was outstanding. He didn’t remotely look like the same pitcher, who had labored so much in recent weeks. Aided by modern technology, which breaks down a pitcher’s arm angle during delivery precisely, it was discovered Nathan had dropped down a bit from last season, when he was one of MLB’s top closers with the Texas Rangers.
His velocity was up Thursday, and he was piecing the borders of each quadrant of the strike zone.
“We missed Joe. We really wanted him back to what he is. It was uplifting,” Ausmus said.
The performance by Sanchez was the second straight excellent one by a Tigers’ starting pitcher (Drew Smyly had one of the best starts of his career despite the loss Wednesday). It came on the heels of back-to-back stinkers by Detroit’s Cy Young duo of Justin Verlander and Max Scherzer, and what had been unanticipated down period for the Tigers’ starters.
Austin Jackson’s hit was significant. As he goes, regardless where he is hitting in the batting order, so do the Tigers’ tend to go offensively.
If age has caught up to Torii Hunter, the options are better for corner outfielder with Andy Dirks coming back at some point sooner instead of later, and the emergence of J.D. Martinez, who looks like a find. He was discarded by the MLB plankton known as the Houston Astros as he approaches salary arbitration eligibility and the pay raise it brings. Their loss has been the Tigers’ gain. He has power and is better than he had been billed defensively.
The Tigers have no such options in center field. They need Austin Jackson at his best. Lately, he has not been.
Ausmus handled himself well under the circumstances. Nobody condones his remark, but it’s impossible to believe it was the result of anything but foot-in-mouth disease we all get now and then. It was a decidedly human mistake.
It wasn’t just the win, either. It was how it unfolded.
Maybe it will mean something good for the Tigers on the nine-game road trip to Cleveland, Texas and Houston. |
In a recent interview to the International Tennis Federation, the Spaniard Rafael Nadal recalled his 2008 Olympic Gold medal that he won beating the Chile's Fernando Gonzalez in straight sets, 6-3 7-6(2) 6-3. It was the first time that a Spanish player won a gold medal at the Games.
Nadal also achieved one in doubles at 2016 Rio de Janeiro alongside Marc Lopez. But speaking about that success in Beijing ten years ago, the current world No. 1 said: 'I felt very big emotions. It is one of the most important victories in my career, without a doubt, so I was just happy about that and I really enjoyed the whole experience in Beijing.
To finish the two weeks there with a victory was so, so special for me. It’s different than any other event but at the same time it is the most difficult event to win, because you’re only going to have maybe one or two, or if you’re lucky, three chances in your career.
So you appreciate the thing that you made it, and those were my thoughts at that moment. I had very high emotions when listening to the national anthem, and at the same time knowing it’s something special. Winning the Olympic gold medal is one of the most important things in my career.
At the end of the day the most important thing is your personal feeling and, for me, that I won the Olympics is at the higher level.' Nadal is proud about this achievement: 'I enjoy knowing that I’m an Olympic champion.
But I don’t think very often about the things that I won. That’s the real thing. I go day by day and I’m happy with all the things that have happened in my career and my life.' ALSO READ: Rafael Nadal: Worse players than David Ferrer won a Grand Slam title |
Before I started doing freelance makeup, I was posting random DIY makeup photos on my Facebook page. Being in the TV industry means I am the number one person to come to for celebrity gossip and news. I am not ashamed to admit that reading gossip sites is my ultimate guilty pleasure. Thus needless to say, I get my makeup inspiration mostly from celebrities.
When I see a picture of a celebrity with makeup that I particularly like, I usually save the pictures and try to emulate it.
So here are some of my less-than-perfect attempts. 😀
Dianna Agron inspired look that she wore to the Grammys. I love the bold dark look that she’s wearing. Very different from her usual ‘Quinn Fabrey’-look that she wears on Glee. I managed the super sharp flick at the corners by using tape as a ruler!
This is the look Beyonce sported in her ‘Party’ music video. I fell in love with the olive green colours that she used. Once again, I managed the sharp flick with tape!
Now this is a makeup look I am not usually very comfortable with. very dark on the eyes with black eyeliner on the lower waterline. But I really like this look by Effy from the TV series ‘Skins’. This was actually requested by a friend, so I decided to give it a shot!
This look is cray cray!! I just needed to use my new MAC Viva Glam Gaga lipstick, and that was why I decided to do this crazy look. I got the colours mostly from my Coastal Scents 88-colour palette!
I love Katy Perry! This was also a request from a friend. I wanted to make the look as wearable as possible…. though I really don’t think this is suitable for a daytime thing. Totally up to personal preference! But I had so much fun doing this!
I hope you guys like these looks! IF you have any requests, then leave a comment! I’ll see if I can try and recreate it! |
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An overdraft occurs when you do not have enough money in your account to cover a transaction, but we pay it anyway. We can cover your overdrafts in two different ways:
We have standard overdraft practices that come with your account.
We also offer overdraft protection plans, such as a link to a savings account, which may be less expensive than our standard overdraft practices. To learn more, ask us about these plans.
This notice explains our standard overdraft practices.
What are the standard overdraft practices that come with my account?
We do authorize and pay overdrafts for the following types of transactions:
Checks and other transactions made using your checking account number
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We do not authorize and pay overdrafts for the following types of transactions unless you ask us to (see below):
ATM transactions
Everyday debit card transactions
We pay overdrafts at our discretion, which means we do not guarantee that we will always authorize and pay any type of transaction.
If we do not authorize and pay an overdraft, your transaction will be declined.
What fees will I be charged if American Southwest Credit Union pays my overdraft?
Also, if your account remains negative for more than 30 days, the account will be considered “not in good standing” and may be closed.
What if I want American Southwest Credit Union to authorize and pay overdrafts on my ATM and everyday debit card transactions?
If you also want us to authorize and pay overdrafts on ATM and everyday debit card transactions, you may opt-in either by signing and returning this form to one of our branches or mailing this form to us at P.O. Box 370, Sierra Vista, AZ 85636.
Once you have opted-in, you may opt-out using any of the above listed methods.
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Your savings federally insured to at least $250,000 and backed by the full faith and credit of the United States Government. National Credit Union Administration, a U.S. Government Agency.
You are now leaving ASCUs web site and are going to a web site that is not operated by the credit union. ASCU is not responsible for the content or availability of linked sites. Please be advised that ASCU does not represent either the third party or you, the member, if you enter into a transaction. Further, the privacy and security policies of the linked site may differ from those practiced by the credit union. |
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About the Author
Rabbi Yaakov Salomon, C.S.W. is a noted psychotherapist, in private practice in Brooklyn, N.Y. for over 25 years. He is a Senior Lecturer and the Creative Director of Aish Hatorah's Discovery Productions. He is also an editor and author for the Artscroll Publishing Series and a member of the Kollel of Yeshiva Torah Vodaath.
In these marvelous stories -- brimming with wit, understanding, a touch of irony and a large helping of authentic Torah perspective -- we will walk with a renowned and experienced psychotherapist and popular author through the pathways of contemporary life: its crowded sidewalks, its pedestrian malls, and the occasional dead end street. This is a walk through our lives that will be fun, entertaining -- and eye-opening. In our full -- sometimes overfull -- and complex lives, Yaakov Salomon is a welcome and much-needed voice of sanity and reason.
His speaking, writing and musical talents have delighted audiences from Harvard to Broadway and everything in between. Rabbi Salomon shares his life with his wife, Temmy, and their unpredictable family.
Visitor Comments: 18
(12)
Brian A.Donnelly,
April 6, 2014 10:59 AM
Muslim muscle.
Hi,As a devout Christian, and therefore a staunch supporter of Israel and the Jewish people, I cannot entirely agree with your position of not allowing Religious topics or subjects to be discussed in schools.Here in Australia we are sadly going the way of Europe and , I hope, to a lesser extent, the USA - we are caving into the incessant demands of the minority muslim population.This recent demand for special foods; prayer rooms; dress codes etc. is simply another way that islam seeks to divide and conquer.The growth of the Halal certification racket is mind blowing in its grab for cash from industry and small business to pay what amounts to extortion for the privilege of carrying a tick of Halal approval. In many cases the food, or service, is not subject to these food laws - but they demand their cut anyway. These semi-criminal proceeds are then used to fund further separationist behaviour and finance terrorist activities.So, whilst I deplore the whole cancer od islam on Western society, I do defend the right of any religion or culture to allow that belief to be openly discussed in the Public school system - provided ALL have the same right.Shalom,Brian.
(11)
Anonymous,
April 6, 2014 5:26 AM
Serve Halal food
Serve Halal food, as well as Kosher, vegetarian, and foods without common allergens. I cannot see how this will result in prayers in classrooms and other religious practices.It seems that we get more sensitive, perhaps not consciously, when we hear about Islam.
(10)
Degel,
April 6, 2014 5:07 AM
Resolution # 54 is a dangerous mistake
So the Muslims got this precedent happened and now it will cause a new serious of problems and headache:1. Polarity among children. Reason for bulling will increase and you would not be able to control that because of the subtle environment 2. In order to fit the suit Muslims might start to claim that they are special, high rank group of children, add to that irrational peer pressure and mob mentality and in a short period of time some of the kids would think that they like to be Muslims… 3. Serving Halal in cafeteria is a dangerous precedent because fanatical terrorists can use this type of dividedness as strategy for their atrocious terrorists attack… now when all Muslims kids are “safe” with Halal food the rest school kids might be poisoned (G0d forbid) by some kind of biological weapon(G0d forbid). There is no winner in this game!
(9)
Bob Van Wagner,
April 4, 2014 8:55 PM
Dangerous and false concept: separation of church and state at the community level
A careful and honest survey of the success and failure of schools will, to my experience, show one key determinant to the success or failure of a school again and again. That key? The level of involvement of the community. A community that is throughly involved in the operation and operating philosophy of the school is far more likely to be a successful one, and a school with no or little community involvement in it will more likely than not be a failure. And what does failure mean? It means that the children will suffer in morals, emotional discipline, learning and intellect.
A community ALWAYS includes a religious, and that includes sectarian, component. In fact, it is formal religion which is the framing and glue that holds communities together.
Especially primary and elementary schools should be very local to properly synchronize with the local community, in that time of life in which the children are developing their moral framework -- in nearly all case that is a framework which must be developed as a whole with the religion of the community.
The founders of the US understood this, that is the way of life they lived. At the time Constitution was written and ratified and the First Amendment discussed and incorporated most states had official religions and communities could and did tax ALL citizens to support not just schools run in a sectarian manner, but even to pay taxes towards the construction and maintenance of Churches. It wasn't until the mid-1800's that official State religions disappeared.
The deplorable modern "Constitutional Law" doctrine of the separation of church and state is one born out of spite and hatred. It is anathema to the original intent. It's inventor, Hugo Black, was a Klan member, who hated Jews, Blacks and Catholics. He ruled to spite the Catholics bussing their kids to Catholic Schools on the taxpayer dime.
(8)
Anonymous,
April 3, 2014 7:11 PM
provide options so students can receive free lunch if they qualify
I teach in a public school. If Halal food is not offered in public city schools many of those students who would qualify for free or partially subsidized lunch would not be able to receive it. These students may depend on receiving free or reduced price lunch in order to have something to eat. I think providing other options such as vegetarian and gluten free are also good ideas. As it is schools provide alternatives to the daily hot lunch meals, so why not give other options as deemed necessary according to the makeup of the student body. We need to remember that not all students can afford to "brown bag" it.
(7)
Anonymous,
April 3, 2014 4:23 PM
halal food in the schools
Providing halal (or kosher or vegetarian) food in the schools, strikes me as a reasonable accommodation for Muslim (or other, as the case may be) students. This differs from offensive and prohibited establishments of religion such as organized prayer in a school or providing facilities for the exclusive use of one group. If the state generally provides free lunches because that is viewed as beneficial to the educational process, especially where parents might not be able to provide appropriate lunches, the state probably is not required, but probably is not prohibited, from making available choices that cater to the needs of different groups. A member of those groups might or might not trust the certification, and issues could arise, as when Hindus discovered to their horror several years ago that a certain national chain's French fries had been sprayed with beef tallow. Some might prefer a system where students who cannot eat the "regular" food got credits that they could exchange for prepackaged foods that met their needs. The question is sometimes easy and sometimes a close one. In prisons, for example, it is easy to conclude that the state must provide food choices and cannot say "just brown-bag it" (i.e., let you families bring in your food or don't land in jail in the first case). In public schools with a small observant Jewish population, the school could well say that the cost for kosher food is not worth the benefit, but once they decide that another group will be accommodated because they are larger and the cost-benefit balance comes out in favor, then nondiscrimination considerations might require paying for kosher etc. for the few that demand it. And there are unintended consequences. There was an interesting story recently in Florida where non-Jews seem to want the kosher food because they think it is more wholesome and tasty.
(6)
Mati,
April 3, 2014 3:11 PM
Kosher food is good for Muslims
so why not serve kosher? On the other hand, why would Jews be in secular schools anyway? They don't belong there and there is no need. On the other hand serving kosher might get secular Jews to think more of their Torah and ancestry. On the other hand.....
michael swanger,
April 3, 2014 6:05 PM
foods served
in public schools should not be specifically kosher or halel. They should, however, not serve forbidden foods such as pork and shellfish. We need not cave into the moslems nor any specific groups. Jews are in public schools often because they cannot afford private schools and they can help set a proper standard of social conduct. Brown bagging is a good suggestion and one which I did often times as a school boy
Rachel,
April 3, 2014 10:35 PM
Public schools are supposed to serve all children
1. Why would Jews be in secular schools? BECAUSE SOME OF US CANNOT AFFORD DAY SCHOOLS. Also, public schools must take all children; they don't refuse to re-enroll kids who are having academic problems.
2. Were I a member of the NYC council or whatever governing body is in charge, and my constituents came to me saying "my children need _______" food choices, I would do my job and try to get it enacted. That's how democracy works.
3. We are talking about food here, not religion. Many children receive free lunches because their families are low income. It's very nice, Rabbi Salomon, that if you didn't like the school lunches you just brought it from home, but not everyone can afford to provide their children with an appropriate lunch.
By the way, "fish on Friday" in all sorts of cafeterias dates back to when Catholics strictly observed the practice of not eating meat on Friday. (This has since been modified by the Church to being required only during the pentitential period of Lent.)
Personally, I think the solution would be to make appropriate food items available a la carte for everyone. This is done in some university and hospital cafeterias now, with sealed sandwiches and sealed microwave entrees available for those who wish to choose kosher, vegetarian, etc.
In any event, the slippery slope argument about allowing students to choose the appropriate food does not seem to violate the First Amendment. Similarly, children who wish to read religious-themed books, dress in garb required by their own faith, etc. are permitted to do so. Reasonable accommodations of individual religious behavior is the standard. This is a far cry from requiring all students to observe communal school prayer.
(5)
Michael,
April 3, 2014 3:03 PM
Seperation of Religion and State
The Rebi is correct. The problem now is we are restricted to bringing foods not prepared commercially to insure that there are no "peanuts" in the mix. So much for P and J sandwiches I also grew up enjoying. One solution is just serve vegetarian foods and let the meats stay home and as the Rebi stated, brown bag it according to the school rules. Nutrition is the key not the religion. Let's stay focused on LUNCH not Halal or Kosher etc.
(4)
Anonymous,
April 2, 2014 9:53 PM
I respectfully disagree
As a Jew, I try to influence the world to magnify and sanctify G-d's name.
Making sure we ignore Him in the public square is incompatible with my mission.
As s Jew, I try to take care of peoples' needs.
Denying food to the hungry is incompatible with my mission.
As a Jew, I only consume kosher cuisine.
A norm mandating convenient availability of such a menu would materially enhance my lifestyle.
Altruistically and selfishly, I applaud New York's model and hope the rest of the world adopts it soon.
Anonymous,
April 4, 2014 2:55 AM
What "you" do is laudable, However, enhancement of anyone's lifestyle should not be a priority in public schools.
(3)
SusanE,
April 2, 2014 8:20 PM
Peanuts Gluten Vegan Meat Dairy Aggggh.
I agree with Rabbi Salomon. If your food is religon special, bring it with you. If the food your children eat is that important, you wouldn't trust it to the schools to provide anyway. Public schools think Pizza and soda is an acceptible lunch for all children. Send lunch with your religious child.
(2)
Anonymous,
April 1, 2014 12:38 PM
Cafeteria food is notoriously high in fat and low in nutrition. What we need to do is to provide HEALTHY food for all children.
DAVID FRANKEL,
April 3, 2014 3:39 PM
ITS NOT ABOUT HIGH FAT LOW NUTRITION ITS ABOUT CHANGING DIET TO CERTAIN GROUP OF PEOPLE LISTEN TO WHAT THE RABBI SAID
(1)
jools,
April 1, 2014 5:03 AM
If we let them eat McDonalds, we can let them eat Hallel/Kosher/Vegetarian
It is naïve to think that we raise our children in totally ideologically neutral environments.
I see very little objection to exposing children to the messages of the corporate world (NIKE, McDonalds) at schools. So why is everyone up in arms when presented with the ideals of religious organizations, whose motivations can be more noble than corporate greed?
Whatever we eat reflects certain values that are decided upon by someone else. Jewish people, more than most, are aware of this.
Anonymous,
April 1, 2014 12:41 PM
I must also comment on what the rabbi said re: bringing lunch from home. Far too many children are living in poverty and their parents do not have adequate food to send from home. Therefore, we MUST provide adequate nutrition at school. As I stated in an earlier post, the school lunches are high in fat and low in nutrition. This deadly combination is one of the reasons we have childhood obesity.
Zelej,
April 4, 2014 2:45 AM
Parents of children living in poverty are usually recipients of food stamps. It is parent's obligation to take care of children's nutritional needs. Schools are for learning. Not for providing "healthy" (or any sectarian) food. . |
1.. Introduction {#sec1}
==================
With the ever-increasing X-ray photon fluxes now available at third-generation synchrotrons, radiation damage inflicted on experimental samples has once again become a concern during macromolecular crystallographic (MX) investigations, leading to failure of a significant number of structure solution attempts. As is now well documented and has been reviewed (Garman, 2010[@bb14]; Holton, 2009[@bb20]), two types of damage are broadly observed. Global damage, perhaps best quantified by the decline in the integrated intensity of the diffraction patterns as data collection proceeds, is apparently governed by processes of a physical nature. It is thought that there is an upper limit to the dose that can be tolerated by a biological crystal, calculated by analogy with observations of radiation damage rates in electron crystallography to be 20 MGy (Gy = J kg^−1^) (Henderson, 1990[@bb17]). An experimental dose limit at 100 K has been determined as 43 MGy, the dose that will halve the initial summed diffraction intensity across all resolution bins, and a maximal value of 30 MGy has been proposed, beyond which biological information is likely to be compromised (Owen *et al.*, 2006[@bb39]).
However, damage to certain specific residues, a chemical phenomenon, is often observed at much lower doses. This specific damage has been reported to occur in a characteristic sequence in a number of metal-free crystals. Disulfide bridges are the first to be impacted, followed by the decarboxylation of aspartate and glutamate residues, loss of the OH group from tyrosines and the scission of the C---S bond in methionines (Burmeister, 2000[@bb7]; Ravelli & McSweeney, 2000[@bb41]; Weik *et al.*, 2000[@bb50]). At 100 K, the only mobile species are presumably electrons (Jones *et al.*, 1987[@bb23]) and positive holes since radicals are widely thought to be immobile below 110 K. Recently published results of experiments in which an absorption peak at 240 nm from an irradiated vitrified crystallization solution was monitored with a microspectrophotometer and postulated to be from (produced from holes in the aqueous solvent) suggests that these radicals are not able to diffuse and recombine until the temperature is raised to around 160 K (Owen *et al.*, 2012[@bb37]). Thus the radiation chemistry mechanisms of specific damage at 100 K are most likely confined to pathways instigated by holes (either in or adjacent to the protein) and mobile electrons. Of course, in media of high acidity these electrons will react rapidly with protons to give hydrogen atoms which are presumably also mobile at cryotemperatures (Shiraishi *et al.*, 1976[@bb47]).
Various efforts have been made to reduce the rate of radiation damage and thus enable useful data collection over longer beam exposures. Cryocooling (Garman & Schneider, 1997[@bb15]) has been reported to offer a damage reduction of approximately a factor of 70 compared with room temperature (RT) studies (Nave & Garman, 2005[@bb35]). However, certain crystals are not suitable for cryogenic studies, such as those of particular viruses, and data can usually only be collected for these samples at RT. Also, *in situ* data collection from crystallization trays is increasingly being used at synchrotron sources and general interest in RT protein crystallography is re-emerging as doubts arise about the conformational bias of protein ensembles that flash cooling may introduce (Fraser *et al.*, 2011[@bb13]). As a result, there is renewed interest in finding innovative and practical solutions to the problem of radiation damage in protein crystallography at both cryogenic temperatures and RT. One promising avenue of research is the use of radical scavengers, intended to intercept damage agents.
Over the last decade, conflicting results have been reported as to the efficacy (or otherwise) of various radical scavengers in reducing the rate of radiation damage in RT and 100 K MX (Murray & Garman, 2002[@bb33]; Kauffmann *et al.*, 2006[@bb26]; Southworth-Davies & Garman, 2007[@bb48]; Nowak *et al.*, 2009[@bb36]; Barker *et al.*, 2009[@bb2]; Macedo *et al.*, 2009[@bb31]; De la Mora *et al.*, 2011[@bb10]; Kmetko *et al.*, 2011[@bb28]). Several different metrics have been used to monitor and quantify the rate of damage, including the loss of diffraction intensity summed over all resolution bins of complete datasets normalized to the total summed intensity of the first data set (*I* ~*n*~/*I* ~0~), the difference in intensity of the same reflection (*R* ~d~) measured at different times (and thus different dose) in the data collection (Diederichs, 2006[@bb11]), and the difference in scaling *B*-factor between consecutive data sets or between repeated 5°-wedges, *B* ~rel~ (Kmetko *et al.*, 2006[@bb27]). It has already been noted that for *I* ~*n*~/*I* ~0~ (De la Mora *et al.*, 2011[@bb10]), and for *B* ~rel~ and *R* ~d~ (Krojer & von Delft, 2011[@bb29]) calculations using different software packages can give different values and thus change the conclusions that can be drawn from the rates of global radiation damage obtained for the same raw data series. Other metrics of global radiation damage include unit cell expansion and crystal mosaicity. However, these appear to be poorly reproducible (Murray & Garman, 2002[@bb33]; Ravelli *et al.*, 2002[@bb42]). It should be noted that the ratio of average intensity of reflections to noise, *I*/σ(*I*), is an inherently biased metric since noise increases with radiation damage (De la Mora *et al.*, 2011[@bb10]).
Significant variation between crystals treated in nominally the same way with scavengers has been observed, with a large scatter in the results. In addition, some scavengers have been tested by several groups and the results are not always in accord. Indeed a number of studies have observed little, or even adverse effects of these additives. For the cases where results from investigations by different researchers conflict, the metrics employed in each study and the resulting conclusions are summarized in Table 1[▶](#table1){ref-type="table"} (a full summary of all scavengers so far tried for MX can be found in the supplementary material, Table S1[1](#fn1){ref-type="fn"}). It can be seen from examination of Table 1[▶](#table1){ref-type="table"} that only two scavengers have been reported to increase the dose tolerance by more than a factor of two, and that there is a lack of consensus on the efficacy of those that have been investigated by various different means. The exceptions are 1,4-benzoquinone at RT and sodium nitrate at 100 K. The former has been observed to increase the dose tolerance to global damage by a factor of nine (Barker *et al.*, 2009[@bb2]) as monitored by intensity decay, and significantly reduce the specific damage to susceptible residues (with some disulfides remaining undamaged). In the latter case the specific damage to disulfides was reduced by more than a factor of five (De la Mora *et al.*, 2011[@bb10]), while the global damage, again assessed from intensity decay, was lessened by a factor of two. Both of these scavengers were tested on chicken egg-white lysozyme (HEWL) crystals.
Here, possible reasons for these ambiguous and inconsistent observations (Table 1[▶](#table1){ref-type="table"}) are identified, analysed and investigated.
Firstly, when assessing global damage, the same diffraction data analysed using the various damage metrics are shown to provide conflicting results as to the crystal dose tolerance, resulting in differing conclusions on scavenger efficacies.
Secondly, the radiation chemistry already taking place in the crystallization buffers upon X-irradiation is shown to strongly compete with any attempts to quench damage agents with added scavengers. The results of complementary microspectrophotometric studies are presented both at cryo- and room temperatures on mounted crystals, the crystallization screens, and also their individual components. It is clear that there is hitherto unexplored interplay between the components in crystallization buffers. This phenomenon greatly affects the reproducibility of the results and offers a further explanation for some of the above-mentioned discrepancies.
Computational chemistry investigations have also been pursued in an effort to shed light on the observed absorption patterns and hence elucidate the fate of damage agents induced in the various supporting media.
Thirdly, it should be noted that the accurate determination of the dose which a crystal has absorbed is a decidedly non-trivial exercise. An estimation of the dose requires detailed information on the characteristics of both the crystal and the beam. For the crystal, the absorption coefficient is determined from knowledge of the sample size and composition (*i.e.* the number of each atom type in the unit cell), and for the incident beam, its energy, size, shape and flux (in photons s^--1^) must be known. For MX, this can be conveniently carried out by means of the program *RADDOSE* (Murray *et al.*, 2004[@bb34]; Paithankar *et al.*, 2009[@bb40]). Detailed considerations of dose and the effects of its distribution are explored elsewhere in this issue (Zeldin *et al.*, 2013[@bb53]).
In addition to these factors, the whole concept of a dose limit based on the arguments of physics is challenged if dose tolerance can be chemically modified by scavengers. Thus it may be time to consider rethinking the current division of effects into 'physical' and 'chemical'. This important question will be revisited in the discussion.
2.. Methods {#sec2}
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2.1.. Re-analysis of 100 K HEWL--sodium-nitrate and HEWL--ascorbate scavenger data using different metrics for global radiation damage {#sec2.1}
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To test the robustness of global damage metrics as a source of the inconsistent scavenger results from different studies, the raw data for which *I*/*I* ~0~ \[obtained from both *SCALA* (Evans, 2006[@bb12]) and *XDS/XSCALE* (Kabsch, 2010[@bb24])\] and *R* ~d~ analyses of full datasets were reported by De la Mora *et al.* (2011[@bb10]) were reanalysed. Using *MOSFLM*, *SCALA*, *CAD* and *SCALEIT* from *CCP4i* (Winn *et al.*, 2011[@bb51]), values were produced for *I*/*I* ~0~ (*SCALA*) and *B* ~rel~ (*SCALEIT*) both from full data sets and from 5° wedges of data at various doses.
The original diffraction data were acquired at the ESRF at 100 K from the samples shown in Table 2[▶](#table2){ref-type="table"} (De la Mora *et al.*, 2011[@bb10]). For the HEWL crystals soaked in 1 *M* sodium nitrate, this scavenger was clearly shown to be effective in supressing specific damage by means of electron density maps, and both ascorbate and nitrate increased the dose tolerance to global damage by around a factor of two.
The HEWL crystals used in the De la Mora *et al.* study were grown using 50 mg ml^−1^ HEWL protein (from Sigma) in 200 m*M* sodium acetate (NaAc) buffer at pH 4.7 mixed with an equal volume of precipitant consisting of 0.2 *M* NaAc buffer at pH 4.7 containing 10% *w*/*v* NaCl. Cryoprotection was achieved by replacing the water in the original precipitant solution by 30% glycerol (*v*/*v*) and soaking the crystals in this for approximately 1 min. HEWL--ascorbate co-crystals were grown by replacing water in the precipitate solution to give a final concentration of 1 *M* sodium ascorbate. The sodium nitrate treated crystals were soaked for 4 min or 8 min in a cryosolution made up as above but with some of the water replaced by scavenger to give a final concentration of 0.5 *M* nitrate.
2.2.. Microspectrophotometry measurements {#sec2.2}
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All microspectrophotometery was performed at the Diamond Light Source. Samples were studied using the same on-line microspectrophotometer (R. L. Owen, private communication), but two different beamlines having different beam profiles were used: I02 with horizontal (H) and vertical (V) FWHM of 110 µm and 70 µm, respectively, at 12.658 keV giving 3 × 10^12^ photons s^−1^ at full transmission, and I24 with FWHMs of either 30 µm (H) and 30 µm (V) or 50 µm (H) and 50 µm (V) at 12.8 keV giving 1 × 10^12^ photons s^−1^ at full transmission.
The on-line off-axis UV--vis microspectrophotometer consists of mirror lenses (Bruker), a halogen/deuterium lamp (Ocean Optics) and two objective lenses mounted at 45° with respect to the X-ray beam, allowing cryostream access. The microspectrophotometer is fitted with a Shamrock 303 imaging spectrograph (Andor) which has a wavelength detection range of 200--760 nm. The dimensions of the light beam at the crystal were 80 µm × 80 µm and the device was fitted with 400 µm- and 200 µm-diameter incoming and outgoing optic fibres, respectively. Spectra were collected over an exposure time of 30 ms with 25 accumulations per spectrum written to disk (*i.e.* 0.75 s per spectrum).
Crystals of HEWL were grown using the same components at slightly different concentrations as those used in the De la Mora *et al.* study: 50 mg ml^−1^ HEWL in 0.1 *M* NaAc at pH 4.8 was mixed with an equal volume 0.1 *M* NaAc at pH 4.8, 1.4 *M* NaCl. Crystals grew in a variety of sizes with cell dimensions of *a* = *b* = 77.78 Å and *c* = 38.45 Å and α = β = γ = 90° in space group *P*4~3~2~1~2. Cubic bovine pancreatic insulin crystals were grown using a lyophilized powder (Sigma I6634) from 20 mg ml^−1^ protein in 0.02 *M* Na~2~HPO~4~, pH 10.4, and 0.01 *M* Na~3~EDTA, mixed with 0.5 *M* Na~2~HPO~4~/Na~3~PO~4~, pH 10.4. Crystals of between 15 × 15 × 15 µm and 70 × 70 × 70 µm grew within 72 h with cell dimension of *a* = 78.9 Å in space group *I*2~1~3.
Scavenger (1 *M* LiNO~3~ or NaNO~3~: final concentration 0.5 *M*) was introduced into the crystals by soaking for 4 min. Both the crystal and solution samples were mounted using normal cryoloops (rayon) open to the air. Initial tests showed that the PET tube usually used in the MiTeGen RT mounting system (Kalinin *et al.*, 2005[@bb25]) to enclose the crystal and prevent dehydration was inappropriate as it caused scattering in the absorption spectra. Therefore, an HC1b humidity-controlling device (Sanchez-Weatherby *et al.*, 2009[@bb44]) was used to prevent dehydration of samples at RT. Samples tested at cryogenic temperatures, which had been cryoprotected (by replacing the water in the original precipitant solution by 30% *v*/*v* glycerol), were held across rayon cryoloops and flash cooled into 100 K gaseous nitrogen.
Absorption spectra were collected using two different protocols: with beam on continuously for 10 or 20 s or with beam on for 2 s and then off for 3 s, the cycle being repeated ten times. Data were analysed using the Andor *SOLIS* software supplied with the microspectrophotometer.
Doses were calculated using *RADDOSE* (version 2) following calibration of each beamline with a 500 µm-thick silicon diode (Hamamatsu) by the method detailed by Owen *et al.* (2009[@bb38]).
2.3.. Computational chemistry {#sec2.3}
-------------------------------
In an effort to identify the sources of the absorption peaks detected by microspectrophotometry during X-irradiation, extensive computational chemistry investigations[2](#fn2){ref-type="fn"} on the individual components and their mixtures were conducted.
The structures of the initial compounds and their various radiolytic products, and intermediates along the path to their production, were determined by density functional theory (DFT) calculations. The standard B3LYP functional (Becke, 1993[@bb4]) was employed with a compact polarized split-valence basis set, denoted 6-31G\*. Geometries were optimized using analytic gradients and the nature of the various stationary points determined by consideration of the analytic Hessian. Ultrafine integration grids were used throughout. The effect of the surrounding environment was modelled using a simple reaction field treatment within the integral equation formalism of the polarized cavity approach (IEFPCM) (Tomasi *et al.*, 1999[@bb49]). The geometries of a subset (lowest energy conformers) of the obtained structures were then further refined using a more flexible 6-311+G(d,p) basis set which also includes diffuse functions on the heavy atoms and polarization functions on the hydrogen atoms. The thermochemical feasibility of various reaction paths was assessed and key transient intermediates, possibly observable by other investigative techniques, were identified.
Absorption spectra characteristic of the various intermediates and products were calculated from time-dependent density functional theory (TD-DFT) (Runge & Gross, 1984[@bb43]) at the corresponding optimized geometries of the species involved, again using a diffuse function augmented (6-31+G\*) basis set and within the same solvent reaction field model.
3.. Results {#sec3}
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3.1.. Re-analysis of HEWL--sodium-nitrate scavenger data using different metrics for global radiation damage {#sec3.1}
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The results of the reanalysis of the previously published HEWL--sodium-nitrate data to extract *B* ~rel~ for whole data sets (Fig. 1*a* [▶](#fig1){ref-type="fig"}) and for 5° wedges (Fig. 1*b* [▶](#fig1){ref-type="fig"}) implied different efficacy of sodium nitrate as a scavenger than was obtained from the original *I*/*I* ~0~ analysis (Fig. 1*c* [▶](#fig1){ref-type="fig"}). From these graphs it is clear that there is a disparity between the metrics. Generally, there is a consistent trend in the results, but the HEWL crystal soaked in nitrate for 8 min can be described as being either less prone or more prone to global radiation damage depending on whether *B* ~rel~ or *I*/*I* ~0~ is used as the metric, respectively. The results also show that *B* ~rel~ derived from 5° wedges of data (*B* ~rel~5) does not give exactly the same description of global damage as *B* ~rel~ derived from whole datasets (*B* ~rel~DS). The general trend is again conserved, but there are notable differences in the suggested extent to which crystal samples are protected from global radiation damage compared with the native crystal. For example, comparisons of the global radiation damage in the ascorbate co-crystal with the native crystal show greater protection when using *B* ~rel~5 as a metric as compared with using *B* ~rel~DS. Previous *R* ~d~ analysis of these data (De la Mora *et al.*, 2011[@bb10]) showed ascorbate to give a 2.5-fold lower increase in decay factor after 20 MGy than that observed in the native crystal. Interestingly, at this dose, agreement is found with the *B* ~rel~5 analysis, which shows a similar level of protection at 20 MGy. The values of *D* ~1/2~ and the Δ*B* ~rel~/Δ*D* resulting from the analyses are given in Table 3(*a*)[▶](#table3){ref-type="table"}.
The intensity (*I*/*I* ~0~) decay data can be compared by defining an enhancement factor, *E* ~I~, for the intensity analysed data as the *D* ~1/2~ (dose required to halve the intensity of the dataset) value for each sample divided by the *D* ~1/2~ value for the native HEWL crystal. Thus *E* ~I~ \> 1 suggests protection from global radiation damage, a value of 1 suggests no difference in susceptibility, and *E* ~I~ \< 1 implies increased sensitivity. For the *B* ~rel~ analysis, a smaller change in *B* ~rel~ with dose indicates lower damage, so the ratio of the gradients of the native to scavenger fitted *B* ~rel~ lines can be used to judge scavenger efficacy (*E* ~B~). Table 3(*b*)[▶](#table3){ref-type="table"} highlights the differences in the extent to which the crystal samples including scavenger are protected from global radiation damage compared with the native crystal, suggested by the different metrics. As can be seen from that table, the *I*/*I* ~0~ metric orders the scavengers' effectiveness as ascorbate \> nitrate II \> nitrate I \> nitrate8, whereas *B* ~rel~5 gives ascorbate \> nitrate II \> nitrate8 \> nitrate I, while *B* ~rel~DS gives nitrate II \> ascorbate \> nitrate8 \> nitrate I.
3.2.. Microspectrophotometry at RT and 100 K {#sec3.2}
----------------------------------------------
The availability of a suitably equipped microspectrophotometer allows the detection of optical absorption changes induced by X-ray irradiation of solutions and crystals both at RT and 100 K. In an attempt to decouple parameters affecting this phenomenon, and thus gain insight into the radiation chemistry, various subsets of the components of the total irradiated volume have been analysed independently. In Fig. 2[▶](#fig2){ref-type="fig"}, the absorption by the cryobuffer, consisting of the mother liquor and glycerol, has been analysed at RT along with those of the separate components and combinations thereof. Fig. 3[▶](#fig3){ref-type="fig"} shows the RT spectrum obtained from 0.5 *M* NaNO~3~ in HEWL cryobuffer (without the protein) before and after irradiation, and Fig. 4 presents RT time traces at selected wavelengths (400 nm and 580 nm) from HEWL solution in cryobuffer.
For HEWL solution at 100 K, the effect of adding scavenger, LiNO~3~, on X-ray-induced spectral changes is demonstrated in Fig. 5, along with time traces at selected wavelengths. Fig. 6 contains time traces at 100 K from irradiated native HEWL crystals. Fig. 7 demonstrates the effect of the addition of an electron scavenger, again LiNO~3~, in insulin crystals at 100 K. The time courses of the absorption are also presented. The observations illustrated in these figures are described in more detail below.
### 3.2.1.. HEWL buffer component analysis {#sec3.2.1}
Absorption peaks observed at RT upon X-ray irradiation of the HEWL mother liquor constituents (Fig. 2[▶](#fig2){ref-type="fig"}) demonstrate that the presence of the cryoprotectant, glycerol, has an effect on the changes in absorbance. At RT the results clearly show that both NaAc and NaCl, alone and in combination, give only a broad low-intensity signal at short wavelength (\<300 nm). Glycerol alone yields a much stronger broad absorbance around 255 nm, a principal contributor which can be assigned to the enol of malonic dialdehyde (MDA) based both on TD-DFT calculations in this work and on values from the literature (Ivanova *et al.*, 2009[@bb21]). However, when glycerol is added to NaAc a clear peak at 270 nm is observed, whereas glycerol with NaCl gives a broader signal at 470 nm.
### 3.2.2.. Investigating the scavenging ability of nitrate at RT {#sec3.2.2}
Before testing the RT radical quenching efficacy of nitrate in HEWL, a 0.5 *M* NaNO~3~ solution in HEWL cryoprotected mother liquor (without any protein) was irradiated and the absorbance monitored. Before irradiation, the absorption spectrum showed only two peaks, known to be characteristic of nitrate: an intense signal at 230 nm extending to lower wavelengths and a much weaker one at 300 nm (Ley, 1928[@bb30]). After irradiation, a 250 nm peak tentatively attributable to NO~3~ ^2−^ \[assignment based on Grätzel *et al.* (1970[@bb16])\] appeared as a large shoulder on the 270 nm peak previously observed from irradiation of acetate and glycerol, but the 470 nm peak seen in the NaCl and glycerol sample (see §3.2.1[](#sec3.2.1){ref-type="sec"}) was quenched. A large shoulder extending upwards in wavelength from the 270 nm peak to around 380 nm was recorded, centred at approximately 340 nm (Fig. 3[▶](#fig3){ref-type="fig"}). Some contribution to this signal is likely to be made by the Cl~2~ ^--^ radical anion which has a substantial extinction coefficient and an absorption peaking at 340 nm (Jayson *et al.*, 1973[@bb22]).
RT time courses at the wavelengths characteristic of disulfide radical anions \[400 nm (Hoffman & Hayon, 1972[@bb18])\] and solvated electrons \[580 nm (McGeehan *et al.*, 2009[@bb32])\] from an irradiated 35 mg ml^−1^ HEWL solution in cryoprotected mother liquor are shown in Figs. 4(*a*) and 4(*b*)[▶](#fig4){ref-type="fig"}. Before irradiation, the absorption spectrum (not shown) showed only a clean peak from the protein at 280 nm, but, upon interaction with X-rays, the 250 nm MDA signal develops and a broad low-intensity 580 nm peak attributable to solvated electrons also appeared. In addition, a shoulder from the 280 nm protein peak extending to a wavelength of 500 nm appeared. This can be assigned as a combination of the 340 nm peak mentioned above with potential contributions from cyclohexadienyl and hydroxycyclohexadienyl radicals, formed from hydroxyl radical attack on the aromatic residues in the protein, in addition to the 400 nm signal expected from the disulfide radical anion. It also possibly obscures any contribution to the absorbance at 470 nm observed from the NaCl/glycerol mixture (§3.2.1[](#sec3.2.1){ref-type="sec"}). Other absorbances noted above for the various combinations of mother liquor components are dwarfed by the intrinsic absorptions due to the protein.
The same solution with 0.5 *M* NaNO~3~ included was then monitored and both the 400 nm and 580 nm peaks were quenched. The time courses of these absorbances with added NaNO~3~ are also displayed in Figs. 4(*a*) and 4(*b*)[▶](#fig4){ref-type="fig"}.
Interestingly, in-house diffraction experiments carried out on a Bruker MicroStar generator and a Mar345 imaging-plate detector on three native and three LiNO~3~-soaked (0.5 *M* for 4 min) HEWL crystals showed no difference between the rate of decrease of *I*/*I* ~0~ (*E* ~I~ = 0.95) but a slight protecting effect if judged by *B* ~rel~5 (ratio of Δ*B*/Δ*D* without and with scavenger, *E* ~B~ = 1.3) or *B* ~rel~DS (1.2) for the two sets of crystals (data not shown). A protective effect of 2.1 (as judged by the *B* ~rel~5 metric) for RT HEWL soaked in 0.1 *M* NaNO~3~ has previously been reported by Kmetko *et al.* (2011[@bb28]). Our observation that nitrate does not significantly modify global damage rates at RT is explored in §4[](#sec4){ref-type="sec"}.
### 3.2.3.. Investigating the scavenging ability of nitrate at 100 K {#sec3.2.3}
Irradiation of a native HEWL cryobuffered protein solution at 100 K results in the formation of peaks at 400 nm and 580 nm in the absorption spectrum \[Figs. 5(*a*) and 5(*b*)[▶](#fig5){ref-type="fig"}\], which are attributed to disulfide anion radicals and solvated electrons, respectively. Figs. 5(*c*) and 5(*d*)[▶](#fig5){ref-type="fig"} show that addition of 0.5 *M* LiNO~3~ to the protein solution quenches these peaks to the baseline levels of absorbance. This suggests that LiNO~3~ efficiently reduces the presence of disulfide radical anions and solvated electrons, as has previously been observed for sodium nitrate at 100 K (De la Mora *et al.*, 2011[@bb10]). For the crystalline HEWL system, a 12 s time series is shown in Fig. 6[▶](#fig6){ref-type="fig"}. Here both peaks are displayed and the initial rapid rise of the solvated electron absorption is followed by a slow decay which apparently feeds the disulfide bond reduction.
As further evidence of the scavenging power of nitrate, irradiation of an insulin crystal at 100 K resulted in a large absorption around 400 nm which was subsequently seen to be quenched in a crystal which had been soaked in 0.5 *M* LiNO~3~ \[Figs. 7(*a*)--7(*d*)[▶](#fig7){ref-type="fig"}\]. The 580 nm peak showed an initial rise in the native sample, but, as with the HEWL crystal described above, decayed with time (Fig. 7*b* [▶](#fig7){ref-type="fig"}).
3.3.. Computational chemistry {#sec3.3}
-------------------------------
In an attempt to identify the carriers of the various absorption features revealed by the microspectrophotometry investigations, characteristics of the radiation chemistry of glycerol were first probed. Further studies were performed on the likely transients from chloride and acetate-containing solutions.
The computations, using the procedure defined in §2.3[](#sec2.3){ref-type="sec"} and thus denoted IEFPCM-B3LYP/6-311+G(d,p), revealed little (\<8 kJ mol^--1^) difference in the energies of the radicals derived from H-abstraction by the radiation-generated hydroxyl radicals at the central or terminal carbon of glycerol. This abstraction reaction is computed to be exothermic by about 100 kJ mol^--1^. On the other hand, H abstraction from the hydroxyl groups is less favourable, with a computed energy gain of about 70 kJ mol^--1^, so that oxygen-centred radicals are presumably less prevalent. Subsequent dehydration of the resulting C-centred radicals, computed to be an energetically favoured process at RT with a release in free energy of around 90 kJ mol^--1^, leads to the almost isoenergetic HC(=O)----CH~2~OH (denoted R1) and --C(=O)--CH~2~OH radicals.
None of the above-mentioned radicals show significant absorptions at wavelengths to the red of 200 nm (*i.e.* wavelengths longer than 200 nm). On the other hand, disproportionation of R1,is computed to lead to 3-hydroxypropanal and the enol of malonic dialdehyde since the reaction is exothermic by 225 kJ mol^−1^. The latter compound is computed as above to have an intense absorption peak at 250 nm and indeed has been cited as the main contributor to absorbance in this region following radiolysis of polyol solutions in general (Ivanova *et al.*, 2009[@bb21]).
A similarly strong absorption band is predicted at 345 nm for the chloride dimer radical anion, , likely to be produced in the radiolysis of concentrated chloride solutions. This value is in agreement with literature reports (Jayson *et al.*, 1973[@bb22]). However, no such peak is detected here, suggesting either that its precursor may be otherwise scavenged or that the species may be too short-lived under the present conditions.
In addition to disproportionations, the carbon-centred radicals mentioned above can undergo dimerizations and cross reactions. Indeed, many of the products of sustained γ-radiolysis containing three, six and nine carbon atoms and varying numbers of O atoms have been previously identified by GCMS techniques (Baugh *et al.*, 1982[@bb3]). Also, in the presence of dissolved molecular oxygen, peroxide radicals are undoubtedly formed by addition at the radical sites. Computational investigations of typical structures of these products followed by evaluation of potential absorption peaks again showed little optical response at wavelengths longer than 200 nm.
4.. Discussion {#sec4}
================
The debate concerning the effectiveness or otherwise of scavengers for use in MX continues, and possible reasons for the disparate results thus far reported have been investigated here. Sources of these conflicting conclusions from such studies include: choice of metric, radiation chemistry in the mother liquors and buffers utilized in MX, and uncertainties in the dose calculations, as well as inter-crystal variation (Owen *et al.*, 2012[@bb37]).
At present there is no unanimously agreed-upon global damage metric, which can make determining and comparing the effectiveness of different scavengers contentious. This is a significant challenge in the field since, as detailed above, different groups have produced conflicting results about the effectiveness of the same scavengers at the same temperatures in MX. The analyses presented here for sodium nitrate at 100 K show that the same data give different results and thus give rise to contrasting conclusions when analysed with different metrics. As has been observed by a number of researchers, there is also significant variation across crystals of the same protein which have nominally undergone the same treatment. It seems apparent that unless a clear enhancement of a factor of two or more in dose tolerance can be established, scavenger results should be treated with caution. Small positive effects are less likely to be reproducible and thus are not useful for general application in MX.
The fact that the global metrics *R* ~d~, *B* ~rel~ and *I*/*I* ~0~ give different results is likely to be because these metrics are reporting on different properties of the crystal. Since *R* ~d~ is calculated following data scaling, and gives the *R* values between reflections measured at different doses, this metric is dominated by non-isomorphism effects caused by unit-cell expansion, movement of the molecule within the unit cell, and structural changes due to specific damage. *B* ~rel~ gives the change in overall scaling parameter for the wedge of data/dataset and is an indication of the average increase in disorder of the molecules in the crystal. Conversely, *I*/*I* ~0~ is a direct measure of the diffraction strength of the crystal and is thus easier to relate directly to the quality and resolution of the electron density maps.
The analysis of the radiation chemistry occurring in the HEWL mother liquor was enabled by an innovative combination of technology; the humidity-controlling device permitted RT solutions to be tested using on-line microspectrophotometry without sample dehydration. The results demonstrate that irradiation of the HEWL cryoprotected mother liquor at RT causes an accumulation of species that absorb at 270 nm and 470 nm. These peaks were not observed when irradiation occurs at 100 K and this is probably a result of limited radiation chemistry during data collection due to reduced diffusion rates of the more bulky reactive radicals at these low temperatures. Since at RT the peaks only appear in the presence of glycerol, it is likely that glycerol radiolysis contributes in some way. At present the species that give rise to these peaks are unknown, but the results suggest that the peak at 470 nm is a consequence of both glycerol and NaCl radiation chemistry, whereas the peak at 270 nm is a consequence of both glycerol and NaAc radiation chemistry. Obvious candidates such as the dichloride radical anion (Cl~2~ ^−^) and the acetate radical (CO~2~ ^−^) have unrelated absorption maxima, with peaks at 340 nm and 350 nm, respectively. Peaks at these wavelengths were not observed in these experiments. Of course, the formation of both of these species is in competition with glycerol, present in much greater abundance, for the reactive hydroxyl radicals which are a primary product of X-ray irradiation.
Extensive computational exploration of the radiation chemistry of glycerol-containing solutions showed a thermochemically feasible route to the production of MDA which absorbs strongly around 250 nm.
The 470 nm peak observed following irradiation of the cryoprotected mother liquor at RT is quenched by the addition of 0.5 *M* sodium nitrate. The radiation chemistry of nitrate in dilute aqueous solution is complex, involving both radicals and radical ions (Gräzel *et al.*, 1970[@bb16]). One-electron reduction of nitrate by radiolytically generated hydrated electrons is very fast (*k* = 9.7 × 10^9^ *M* ^−1^ s^−1^) and the species formed, NO~3~ ^2−^, typically decomposes *via* an acid-catalysed equilibrium to give NO~2~ (Grätzel *et al.*, 1970[@bb16]). The resulting radical rapidly reacts with hydroxyl to give nitric acid, HNO~3~, which can presumably deprotonate to regenerate the nitrate ion. Similar reactions no doubt proceed in the mother liquor, though many other sinks, such as glycerol and chloride ion, are available for the hydroxyl radical. However, nitrate remains as an effective scavenger for electrons and can be predicted to quench specific damage otherwise caused by these agents. On the other hand the radicals formed upon reaction of nitrate with electrons can themselves, at least at RT, damage proteins, for example by addition to aromatic residues (Shi *et al.*, 2011[@bb46]). It is less clear then that any reduction in global damage might be expected, as indeed borne out by our in-house RT tests (see above). However, these products are presumably not mobile at 100 K where nitrate has been shown to be very effective in quenching specific damage to disulfide bonds in HEWL crystals and offered some reduction in the rate of global damage (De la Mora *et al.*, 2011[@bb10]). In fact, further support for the scavenging role of nitrate at 100 K is evident in the results presented by Macedo *et al.* (2009[@bb31]) who observed differences in the absorbance of cryobuffers intended for use in cryocooling azurin and myoglobin crystals though did not comment on their cause. No peak attributable to the solvated electron was observed in the azurin cryobuffer, likely due to the presence of 1 *M* lithium nitrate as a precipitant.
In order to rationalize the disparate scavenger studies summarized in Tables 1[▶](#table1){ref-type="table"} and S1, it is thus of crucial importance to be aware that many crystallization buffers already contain efficient electron or radical scavengers. reaction rate constants in aqueous solutions at RT for the 14 salts and 14 aqueous organic compounds most frequently reported in the PDB (<http://www.douglas.co.uk/top14.htm>) are given in Table 4[▶](#table4){ref-type="table"}. On the other hand, none of these compounds react at significant rates with the hydrated electron. Clearly, careful account of the various concentrations of all cryobuffer and mother liquor components must be made in order to acquire consistent quantitative data on scavenger efficacy.
An example of the potential pitfalls in drawing conclusions from scavenger studies where crystallization agents with scavenging properties are included in the buffer is apparent from a study of the information collated in Table S1. As already mentioned, at 100 K, only electron and hole scavengers are expected to be effective. Macedo *et al.* (2009[@bb31]) reported that 0.1 *M* potassium hexacyanoferrate(III) (KF) was effective in quenching reduction of the copper in soaked azurin crystals, as shown by the persistence of a 632 nm absorbance peak characteristic of the non-reduced form for longer than it survived in native crystals. However, the crystallization buffer contained 0.5 *M* LiNO~3~, which may well have contributed to the observed effect by scavenging electrons which would otherwise have reduced the copper bound to the azurin. This would have been true for all the scavengers tested on azurin in that study, but perhaps the scavengers reported as ineffective (see Table S1) in the Macedo *et al.* study were in fact sensitizing the crystals and the LiNO~3~ was compensating for their effect. However, the authors also reported that KF decreased the rate of reduction of Fe^3+^ to Fe^2+^ in myoglobin crystals, which were not grown in LiNO~3~, so the picture is once again not completely clear.
Cryoprotectants such as glycerol also interact rapidly with hydroxyl radicals and would potentially cloud any experimental attempts to intercept the radical at low temperatures. In addition, under the usual crystallographic cryoconditions (100 K), is thought to be immobile, and indeed a spectrum putatively assigned to the radical has just been reported in X-irradiated amorphous ice (Owen *et al.*, 2012[@bb37]). Thus hydroxyl radical scavengers would not be expected to give any extra protection at 100 K.
A corollary to the debate around scavenger efficacy is pertinent to the question of whether or not a dose limit related to the decay of diffraction intensity really exists for protein crystals. The points raised above imply that chemical modification of the experimental dose limit of 30 MGy determined at 100 K (Owen *et al.*, 2006[@bb39]) is indeed possible, but only if an electron or hole scavenger is present, since these are thought to be the only mobile species contributing to damage at this temperature.
It is clear that more studies are required to understand the radiation chemistry that is occurring at RT in these samples; however, the basic methodology has now been established for using on-line microspectrophotometry in conjunction with a humidifying device to look at radiation chemistry in RT MX. A more refined understanding of both this and the mechanisms dominant at 100 K will lead to sharper insights into the radiation damage dependent factors limiting data collection under cryoconditions.
5.. Conclusions {#sec5}
=================
The conflicting results from scavenger studies most probably arise from a number of factors, which include the use of different metrics, mother liquor radiation chemistry, and, of course, uncertainties in dose estimation.
Results from several studies certainly indicate the efficacy of scavengers in reducing certain types of specific damage both at cryotemperatures and RT, and of reducing the rate of global damage by more than a factor of two at RT. From the measurements reported above at RT using a humidity-controlling device and a microspectrophotometer, it is clear that the production of various species can be quenched by the addition of radical scavengers. However, it is less clear that this observation can be translated into a significant gain in crystal dose tolerance. Apart from 1,4-benzoquinone at RT, no scavenger at RT or 100 K has been reported to increase crystal dose tolerance by more than a factor of two. However, it is worth considering their use for specific cases.
Constituents of many crystallization buffers clearly interact with the various radiation-induced radicals which would otherwise increase the rate of specific damage. Conversely, screening the most common crystallization conditions for components that could intercept these reactive species may provide crystallographers with valuable information that may go some way toward decreasing radiation damage and enabling clear guidelines to be suggested for the scavenger approach to its mitigation.
Likely sources for some of the absorption profiles observed in microspectrophotometry have been identified using computational chemistry, but a clear identification of all of the peaks observed in the mother liquor components has remained elusive thus far.
Scavengers can only be useful as a mitigation strategy if clearer conclusions emerge and, with them, some general guidelines can be offered to MX experimenters on what might be attempted in order to extend the irradiation life (dose tolerance) of their crystals.
Supplementary Material
======================
######
Click here for additional data file.
Supplementary material file. DOI: [10.1107/S0909049512046237/xh5038sup1.pdf](http://dx.doi.org/10.1107/S0909049512046237/xh5038sup1.pdf)
Supplementary data for this paper are available from the IUCr electronic archives (Reference: [XH5038](http://scripts.iucr.org/cgi-bin/sendsup?xh5038sup1.pdf)). Services for accessing these data are described at the back of the journal.
All computations were performed with the *Gaussian09* software package (Frisch *et al.*, 2009; for reference see supplementary material).
We thank Diamond Light Source (DLS) for beam time, Robin Owen for invaluable data collection assistance on beamline I24, Juan Sanchez-Weatherby for his expertise with the dehumidifier and in data collection on DLS I02, Andrew Bissette for compiling an early version of Table 1[▶](#table1){ref-type="table"}, Ed Lowe for in-house support, Markus Gerstel for help with in-house beam profiling, and the Wellcome Trust (088287/Z/09/Z) for providing funding for our in-house X-ray equipment. The NDRL is supported by the Division of Chemical Sciences, Geosciences and Biosciences, Basic Energy Sciences, Office of Science, US Department of Energy through grant number DE-FC02-04ER15533. This is contribution number NDRL-4940 from the Notre Dame Radiation Laboratory.
![Results of a reanalysis of the data reported by De la Mora *et al.* (2011[@bb10]). (*a*) *B* ~rel~ for whole data sets and (*b*) for 5° wedges, and (*c*) the *I*/*I* ~0~ analysis.](s-20-00023-fig1){#fig1}
{#fig2}
{#fig3}
{#fig4}
{#fig5}
{#fig6}
{#fig7}
###### Mother liquor conditions and results for reported MX scavenger studies where the results from different researchers are inconsistent
Int = introduction: C = co-crystal, S = soak, N/A = not applicable. Damage: G = global damage, Sp = specific damage. Res = response: N = null, P = positive, S = sensitizing, U = unclear. Damage metrics: A\#\#\# nm = absorbance peak detected by microspectrophotometry at the specified wavelength, \|*F* ~*n*~ − *F* ~0~\| = difference electron density maps calculated from the difference in structure factors for the *n*th dataset and first dataset. The other metrics are defined in the text.
Scavenger Concentration of scavenger Temperature System[†](#tfn1){ref-type="table-fn"} Int Conditions Damage Metric Res
---------------------------------------- ----------------------------- ----------------------------------------- -------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------- -------------------------------- ------------------------------------ -----
1,4-Benzoquinone 0.4 *M* 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.75 *M* NaOH, 30% *v/v* EG, pH 13.3 Sp A400 nm P
0.5 *M* RT Tetragonal HEWL crystals^*b*^ S 0.1 *M* NaAc pH 4.5, 4--8% *w/v* NaCl G Average *I*/*I* ~0~ P
Saturated 100 K Azurin crystals^*c*^ S 5 m*M* NaAc pH 5.8, 1.85--1.95 *M* (NH~4~)~2~SO~4~, 0.5 *M* LiNO~3~ Sp A632 nm N
Saturated 100 K Myoglobin crystals^*c*^ S 50 m*M* Tris-HCl pH 7.2--7.4, 1.5--1.6 *M* (NH~4~)~2~SO~4~, 2.25% *v/v* PEG Sp A413--A427 nm, A500--A700 nm N
2-Hydroxyethyl methacrylate (HEMA) 0.01 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.01 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Ascorbate \>0.3 *M* 100 K Tetragonal HEWL crystals^*e*^ C 0.2 *M* NaAc pH 4.7 3--7% *w/v* NaCl, 20% *v/v* glycerol Sp A400 nm P
0.5 *M* 100 K N9 neuraminidase crystals^*f*^ S 1.7 *M* potassium phosphate 40% *v/v* glycerol G Average *I*/*I* ~0~, unit cell P
Sp \|*F* ~*n*~\| − \|*F* ~0~\|
0.8 *M* 92 K Free SeMet-containing solutions^*g*^ N/A 25 m*M* SeMet, 25% *v/v* glycerol Sp XANES *D* ~1/2~ P
0.3 *M* 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.75 *M* NaOH, 30% *v/v* EG, pH 12.9 Sp A400 nm P
0.5 *M* RT Tetragonal HEWL crystals^*b*^ C 0.1 *M* NaAc pH 4.5, 4--8% *w/v* NaCl G Average *I*/*I* ~0~ P
Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
0.2 *M* 100 K Azurin crystals^*c*^ S 5 m*M* NaAc pH 5.8, 1.85--1.95 *M* (NH~4~)~2~SO~4~, 0.5 *M* LiNO~3~ Sp A632 nm P
Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G Average *I*/*I* ~0~ P
0.2 *M* 100 K Myoglobin crystals^*c*^ S 50 m*M* Tris-HCl pH 7.2--7.4, 1.5--1.6 *M* (NH~4~)~2~SO~4~, 2.25% *v/v* PEG Sp A413--A427 nm, A500--A700 nm N
1.0 *M* 100 K Tetragonal HEWL crystals^*h*^ C 0.1 *M* NaAc pH 4.7, 10% *w/v* NaCl, 30% *v/v* glycerol Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G Average *I*/*I* ~0~ P
0.1 *M* RT, 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Cysteine 0.2 *M* 100 K Azurin crystals^*c*^ S 5 m*M* NaAc pH 5.8, 1.85--1.95 *M* (NH~4~)~2~SO~4~, 0.5 *M* LiNO~3~ Sp A632 nm N
\|*F* ~*n*~\| − \|*F* ~0~\| N
0.2 *M* 100 K Myoglobin crystals^*c*^ S 50 m*M* Tris-HCl pH 7.2--7.4, 1.5--1.6 *M* (NH~4~)~2~SO~4~, 2.25% *v/v* PEG Sp A413--A427 nm, A500--A700 nm N
0.1 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.1 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
DTNB 0.2 *M* 100 K Tetragonal HEWL crystals^*i*^ S 25 m*M* NaAc pH 4.5, 5% *w/v* NaCl Sp \|*F* ~*n*~\| − \|*F* ~0~\| U
G *R* ~d~ P
0.2 *M* 100 K PPE crystals^*i*^ S 50 m*M* NaAc pH 5.1, 100 m*M* sodium citrate, 20 m*M* CaCl~2~ Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G *R* ~d~ P
0.2 *M* 100 K Thaumatin crystals^*i*^ S 50 m*M* ADA pH 6.5, 500 m*M* sodium/potassium tartrate Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G *R* ~d~ P
Glutathione (oxidized) 0.2 *M* 100 K Tetragonal HEWL crystals^*i*^ S 25 m*M* NaAc pH 4.5, 5% *w/v* NaCl G *R* ~d~ N
0.2 *M* 100 K PPE crystals^*i*^ S 50 m*M* NaAc pH 5.1, 100 m*M* sodium citrate, 20 m*M* CaCl~2~ Sp \|*F* ~*n*~\| − \|*F* ~0~\| N
G *R* ~d~ S
0.2 *M* 100 K Thaumatin crystals^*i*^ S 50 m*M* ADA pH 6.5, 500 m*M* sodium/potassium tartrate Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G *R* ~d~
HEPES 0.5 *M* 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.5 *M* NaOH, 30% *v/v* EG, pH 9.66 Sp A400 nm N
0.2 *M* 100 K Azurin crystals^*c*^ S 5 m*M* NaAc pH 5.8, 1.85--1.95 *M* (NH~4~)~2~SO~4~, 0.5 *M* LiNO~3~ Sp A632 nm U
\|*F* ~*n*~\| − \|*F* ~0~\| U
Hydroquinone 0.1 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.1 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Nicotinic acid 0.2 *M* 100 K Tetragonal HEWL crystals^*i*^ S 25 m*M* NaAc pH 4.5, 5% *w/v* NaCl Sp \|*F* ~*n*~\| − \|*F* ~0~\| U
G *R* ~d~ P
0.2 *M* 100 K PPE crystals^*i*^ S 50 m*M* NaAc pH 5.1, 100 m*M* sodium citrate, 20 m*M* CaCl~2~ Sp \|*F* ~*n*~\| − \|*F* ~0~\| U
G *R* ~d~ P
0.2 *M* 100 K Thaumatin crystals^*i*^ S 50 m*M* ADA pH 6.5, 500 m*M* sodium/potassium tartrate Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G *R* ~d~ P
0.15 *M* 100 K Bovine pancreatic trypsin crystals^*j*^ S 2.5 mg ml^−1^ benzamidine, 15 m*M* HEPES, pH 7.0 1.5 m*M* CaCl~2,~ 10% PEG 8 K 50 m*M* cacodylate pH 6.5 100 m*M* ammonium sulfate 7.5% glycerol G *R* ~d~ N
*N*-*tert*-Butyl-α-phenylnitrone (PBN) 0.16 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.16 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
PEG 4000 15% 100 K Canavalin crystals^*k*^ S 0.7% NaCl G Average *I*/*I* ~0~ P
20% 100 K Fructose 1,6 diphosphatase^*k*^ S -- G Average *I*/*I* ~0~ P
12%, 45% 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.75 *M* NaOH, 30% *v/v* glycerol, pH 13.59, 13.70 Sp A400 nm N
0.1 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.1 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Reduced DTT 0.5 *M* 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.5 *M* NaOH, 30% *v/v* EG, pH 9.5 Sp A400 nm U
Sodium nitrate 0.02 *M* 195 K *β*-Galactosidase solutions^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide U
0.02 *M* RT β-Galactosidase solutions^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide N
1 *M* 92 K Free SeMet-containing solutions^*g*^ N/A 25 m*M* SeMet, 25% *v/v* glycerol Sp XANES *D* ~1/2~ P
1% 40 K Tetragonal HEWL crystals^*m*^ C 50 m*M* NaAc pH 4.5, 0.25 *M* NaCl 30% *v/v* EG Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
0.5 *M* 100 K Tetragonal HEWL crystals^*h*^ S 0.1 *M* NaAc pH 4.7, 10% *w/v* NaCl, 30% *v/v* glycerol Sp A400 nm P
Sp \|*F* ~*n*~\| − \|*F* ~0~\| P
G *I*/*I* ~0~ P
0.1 *M* RT Tetragonal HEWL crystals^*d*^ S 0.5 *M* NaCl G Δ*B* ~rel~ P
0.1 *M* 100 K Tetragonal HEWL crystals^*d*^ S 0.5 *M* NaCl G Δ*B* ~rel~ N
Styrene 0.002 *M* RT DOB immunoglobulin crystals^*n*,*o*^ C 70% 0.1 *M* sodium borate, pH 8.4 G *I*/*I* ~0~ for 2 or 3 reflections P
Saturated 100 K Tetragonal HEWL crystals^*e*^ C 25 m*M* NaAc pH 4.5, 0.5 *M* NaCl, 30% MPEG 5K 10% *v/v* glycerol Sp \|*F* ~*n*~\| − \|*F* ~0~\| N
G Average *I*/*I* ~0~ N
0.1 *M* RT Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ S
0.1 *M* 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Thiourea 0.5 *M* 100 K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.25 *M* NaOH, 30% *v/v* EG, pH 10.87 Sp A400 nm U
0.2 *M* 100 K Azurin crystals^*c*^ S 5 m*M* NaAc pH 5.8, 1.85--1.95 *M* (NH~4~)~2~SO~4~, 0.5 *M* LiNO~3~ G A632 nm U
0.4 *M* RT, 100 K Tetragonal HEWL crystals^*d*^ C 0.5 *M* NaCl G Δ*B* ~rel~ N
Trehalose 1 *M* 100K Disulfide/thiol model solutions^*a*^ N/A 0.1 *M* cystine, 0.25 *M* NaOH, 30% *v/v* glycerol, pH 12.1 Sp A400 nm N
Tris 0.02 *M* RT β-Galactosidase solutions^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide P
0.02 *M* 195 K β-Galactosidase solutions^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide N
0.02 *M* RT β-Galactosidase lyophilisized powders^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide P
0.02 *M* 195 K β-Galactosidase lyophilisized powders^*l*^ N/A 0.01 *M* phosphate, pH 8.0 Sp Mass of native polypeptide N
^*a*^Southworth-Davies & Garman (2007[@bb48]). ^*b*^Barker *et al.* (2009[@bb2]). ^*c*^Macedo *et al.* (2009[@bb31]). ^*d*^Kmetko *et al.* (2011[@bb28]). ^*e*^Murray & Garman (2002[@bb33]). ^*f*^Betts (2003[@bb5]). ^*g*^Holton (2007[@bb19]). ^*h*^De la Mora *et al.* (2011[@bb10]). ^*i*^Kauffmann *et al.* (2006[@bb26]). ^*j*^Nowak *et al.* (2009[@bb36]). ^*k*^Cascio *et al.* (1984[@bb9]). ^*l*^Audette-Stuart *et al.* (2005[@bb1]). ^*m*^Borek *et al.* (2007[@bb6]). ^*n*^Zaloga & Sarma (1974[@bb52]). ^*o*^Sarma & Zaloga (1975[@bb45]).
###### Crystals from which data were previously collected at 100 K (De la Mora *et al.*, 2011[@bb10])
For data collection statistics see Table 2 of De la Mora *et al.* (2011[@bb10]).
Sample name Crystal Soaked/co-crystallized with scavenger Scavenger (number of datasets)
---------------------------- --------- --------------------------------------- --------------------------------------------------
Native HEWL HEWL N/A None (6)
HEWL--ascorbate co-crystal HEWL Co-crystallized Ascorbate (6)
HEWL + Nitrate I HEWL Soaked for 4 min Sodium nitrate (final concentration 0.5 *M*) (5)
HEWL + Nitrate II HEWL Soaked for 4 min Sodium nitrate (final concentration 0.5 *M*) (6)
HEWL + Nitrate8 HEWL Soaked for 8 min Sodium nitrate (final concentration 0.5 *M*) (6)
###### Reanalysis of the data reported by De la Mora *et al.* (2011[@bb10])
######
The values of *D* ~1/2~ and Δ*B* ~rel~/Δ*D* (slope of *D versus B* ~rel~ graph) resulting from the reanalysis described in the text.
Metric Δ*B* ~rel~ /Δ*D* (Å^2^ MGy^−1^) *D* ~1/2~ (MGy)
--------------------------------- --------------------------------- ----------------- ------
Native HEWL 1.04 0.98 12.6
HEWL + Nitrate I 0.68 0.83 18.8
HEWL + Nitrate II 0.41 0.46 21.2
Mean of HEWL + Nitrate I and II 0.55 0.65 20.0
HEWL + Nitrate8 0.52 0.55 10.4
HEWL-ascorbate co-crystal 0.39 0.53 24.0
######
The enhancement factors, *E* ~*B*~ and *E* ~*I*~, obtained using the two different metrics.[†](#tfn2){ref-type="table-fn"}
Enhancement factor (a.u.) *E* ~*B*~ *E* ~*B*~ *E* ~*I*~
---------------------------- ----------- ----------- -----------
HEWL + Nitrate I 1.53 1.18 1.44
HEWL + Nitrate II 2.54 2.13 1.68
Mean Nitrate I and II 1.90 1.52 1.59
HEWL + Nitrate8 2.01 1.77 0.83
HEWL--ascorbate co-crystal 2.65 1.86 1.90
For *I*/*I* ~0~, this is defined as the ratio of *D* ~1/2~ (dose to half intensity) with scavenger added to *D* ~1/2~ of the native. For the *B* ~rel~ analysis, the enhancement factor is the ratio of Δ*B* ~rel~/*ΔD* without scavenger to Δ*B* ~rel~/Δ*D* with scavenger (thus a value \>1 implies some protection).
###### Rates of reaction with the 14 most frequently reported crystallization mother liquor component salts and 14 organic aqueous solvents in the survey of the PDB reported at <http://www.douglas.co.uk/top14.htm>
No. of entries Average concentration (% *v*/*v*) Rate (*M* ^−1^ s^−1^)[†](#tfn3){ref-type="table-fn"}
------------------------------------- ---------------- ----------------------------------- ------------------------------------------------------
Organic precipitants (2503 samples)
PEG 4K 710 21.1 ∼3 × 10^9^
PEG 8K 488 18.1 \"
PEG 3.5K 296 20.5 \"
PEG 6K 212 16.8 \"
MPD 193 38.6 ∼6 × 10^8^
PEG 400 142 25.7 ∼3 × 10^9^
PEG-MME 2000 65 22.7 \"
PEG-MME 5000 63 20.0 \"
PEG 1000 57 19.8 \"
2-Propanol 48 18.0 2.0 × 10^9^
PEG 2000 45 22.3 ∼3 × 10^9^
Ethylene glycol 43 20.5 2.4 × 10^9^
Ethanol 43 28.8 2.0 × 10^9^
PEG 10K 32 22.0 ∼3 × 10^9^
No. of entries Average concentration (*M*) Rate (*M* ^−1^ s^−1^)[†](#tfn3){ref-type="table-fn"}
--------------------------------- ---------------- ----------------------------- ------------------------------------------------------
Salt precipitant (1436 samples)
Ammonium sulfate 900 1.9 \*
Sodium chloride 124 1.7 3.0 × 10^9^
Sodium citrate 76 1.1 1.5 × 10^8^
Sodium/potassium phosphate 66 1.8 \*
Lithium sulfate 63 1.4 \*
Sodium formate 59 3.4 3.2 × 10^9^
Magnesium sulfate 29 1.7 \*
Ammonium phosphate 29 1.5 \*
Potassium phosphate 25 2.0 \*
Sodium acetate 21 1.2 1.0 × 10^8^
Sodium/potassium tartrate 13 1.0 1.4 × 10^9^
Caesium chloride 11 2.7 3.0 × 10^9^
Potassium chloride 10 1.4 3.0 × 10^9^
Sodium phosphate 10 1.4 \*
Experimentally determined rates in dilute aqueous solution at RT (Buxton *et al.*, 1988[@bb8]). \*Reaction too slow to be detected.
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Euro to Indian Rupee Converter Calculator
This EUR to INR converter is up to date with rates from 03/20/2018 00:59:18 i These conversions are made using the Interbank rate. It should be used as a reference only.
Today 1 Euro is worth 80.48401 INR while 1 Indian Rupee is worth 0.01242 EUR.
Euro / Indian Rupee ratio is the value of the Euro in Indian Rupee. EUR/INR thus refers to the exchange rate of the Euro in Indian Rupee, ie the value of the European currency expressed in Indian currency. The notation used is EUR / INR, but there are others, such as EURINR or EUR-INR. The symbol for EUR can be written €.The symbol for INR can be written Rs. The India country code is IND or INInstructions: Enter the amount of Euro to be converted in the box to the left. Choose the home currency by clicking on the currency name in the box to the right. To change from Euro (foreign) to another currency, just click on the currency name in the box to the left.
How Do I Choose the Rate That Applies to Me?
The currency exchange rates here and in other sites is based on "interbank exchange rates". These rates are based on trading in a global network of more than 1,000 banks, and are not available through consumer or retail channels.
Consumers may use these rates as a reference only. To obtain actual retail rates, contact your local financial institution or currency exchange.
Retail spreads (the difference between the bid and ask prices) for smaller amounts are not reflected in these interbank prices since they vary among payment systems, countries and banks.
For these retail rates use this formula:
Value you will pay = value you get in this converter + X% (due to the margin for the cost of the exchange services).
The value X% varies from 1 to 10% or even more and depends on many factors. Examples:
1 - ATMs typically add 2 percent;
2 - Credit cards typically add 2 to 3 percent;
3 - Banks and foreign exchange kiosks add around 5%;
4 - Some Internet based foreign currency exchange agencies add 11 percent or even more.
How and where to exchange currency?
When it comes to exchange rates, you should know all your options. The practice can vary from country to country. In one country, you may have to change your money at the airport, and in other countries you may need to buy your foreign currency in advance. All options have its pros and cons. Perhaps the easiest way is to visit your bank – almost all banks can convert your home currency to dollars, Euros, Pounds and other major currencies. Anything outside these most popular currencies, you should visit a larger CBD branch for this. You could also use services like American Express or Travelex.
About Indian Rupee (INR)
The INR - Indian Rupee - is the official currency of the India in Asia. There are 100 paise in each 1 Rupee ( its sub-unit ). The symbol for INR is Rs. India was one of the earliest issuers of coins (circa 6th century BC). The first 'rupee' introduced by Sher Shah Suri was based on a ratio of 40 copper pieces (paisa) per rupee. The currency is known as the rupee, roopayi, rupaye, rubai or other terms derived from the Sanskrit rupyakam. The most commonly used symbols for the rupee are Rs, Rp and रू.
About Euro (EUR)
The EUR - Euro - is the standard monetary unit of the Eurozone in Europe. There are 100 cents in each 1 Euro ( its sub-unit ). The symbol for EUR is €. The countries in the eurozone are: Austria , Belgium, Cyprus, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Latvia, Luxembourg, Malta, The Netherlands, Portugal, Slovakia, Slovenia and Spain. Monaco, San Marino, the Vatican City and Andorra use the euro as their official currency and issue their own coins. Some states, like Kosovo and Montenegro, have adopted the euro unilaterally, althoug they do not form part of the Eurozone. |
Q:
Can running a browser in Windows Compatibility Mode be a security issue?
I have several clients that are having trouble logging into vendor's web service. When talking to the vendor about the issue, they told me to set them up with Chrome running in Windows XP compatibility mode. This is how they want the client to change the compatibility settings:
I have some reservations about this fix workaround, given that Microsoft does not support Windows XP anymore (unless you pay for it). Can running a browser in Windows compatibility mode be a security issue?
A:
There are a few things that are enabled when setting compatibility mode, such as shimming.
There are also other changes that may impact on security:-
There have also been some other changes from Windows version to Windows version. In older versions for example, if a programm [sic] loaded a DLL, the search path for the DLL also included the current directory. This is a security issue, so newer versions of Windows by default don't search in the current directory. With the proper shim you can simulate the old behaviour.
This would normally only be a security issue for the local machine if an unprivileged user had permission to copy a malicious DLL to the Chrome installation folder it could be loaded in place of the normally loaded DLL and be executed when a privileged user next ran Chrome (although UAC would still mitigate the damage as this will still apply in compatibility mode).
The attacker would of course need access to the machine, and would need a perfect storm of misconfiguration to succeed. There are no vulnerabilities in the compatibility mode changes that I know of that would enable an attack on the client to succeed from the web where it would not normally succeed without compatibility mode.
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Q:
Storing password (functions.php)
I have created password form where visitors can access any password protected post with belonging password. Basically you enter unique password and you are redirected to a post which is protected with given password.
Everything works fine (with help from s_ha_dum), except one thing - you have to enter password twice.
functions.php :
function doPasswordStuff(){
if(isset($_POST['homepagepassword'])){
global $wpdb;
$post_password = trim($_POST['passwordfield']);
$post_id = $wpdb->get_var( $wpdb->prepare("SELECT ID FROM $wpdb->posts WHERE post_password = %s", $post_password) );
if (!empty($post_id)) {
wp_redirect(get_permalink($post_id));
exit();
} else {
// oh dear, there isnt a post with this 'password', put a redirect to a fallback here
wp_redirect(xxx');
exit();
}
wp_reset_query();
}
}
add_action('template_redirect','doPasswordStuff');
Do you have any idea how to do this without entering password twice?
A:
Here ya go:
function dopasswordstuff(){
if(isset($_POST['homepagepassword'])) {
global $wpdb;
$post_password = trim($_POST['passwordfield']);
$post_id = $wpdb->get_var( $wpdb->prepare("SELECT ID FROM $wpdb->posts WHERE post_password = %s", $post_password) );
if (!empty($post_id)) {
if ( empty( $wp_hasher ) ) {
require_once( ABSPATH . 'wp-includes/class-phpass.php' );
// By default, use the portable hash from phpass
$wp_hasher = new PasswordHash(8, true);
}
// 10 days
setcookie( 'wp-postpass_' . COOKIEHASH, $wp_hasher->HashPassword( stripslashes( $post_password ) ), time() + 864000, COOKIEPATH );
wp_redirect(get_permalink($post_id));
}
exit;
}
}
add_action('template_redirect','dopasswordstuff');
I cribbed some stuff from the Core post login system and I believe I got it working. The trick is to set the cookie, which required adding this part:
if ( empty( $wp_hasher ) ) {
require_once( ABSPATH . 'wp-includes/class-phpass.php' );
// By default, use the portable hash from phpass
$wp_hasher = new PasswordHash(8, true);
}
// 10 days
setcookie( 'wp-postpass_' . COOKIEHASH, $wp_hasher->HashPassword( stripslashes( $post_password ) ), time() + 864000, COOKIEPATH );
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Q:
Comparing Json data. Python 3
I have the following Json file and I need to compare data to see how many times each value repeat itself. The problem is, I have no idea about handling Json. I don't want the answer to my exercise, I want to know how to access the data. Json:
{
"tickets": [
{
"ticket_id": 0,
"timestamp": "2016/05/26 04:47:02",
"file_hash": "c9d4e03c5632416f",
"src_ip": "6.19.128.119",
"dst_ip": "145.231.76.44"
},
{
"ticket_id": 1,
"timestamp": "2017/05/28 16:14:22",
"file_hash": "ce8a056490a3fd3c",
"src_ip": "100.139.125.30",
"dst_ip": "145.231.76.44"
},
{
"ticket_id": 2,
"timestamp": "2015/08/23 03:27:10",
"file_hash": "d17f572496f48a11",
"src_ip": "67.153.41.75",
"dst_ip": "239.168.56.243"
},
{
"ticket_id": 3,
"timestamp": "2016/02/26 14:01:33",
"file_hash": "3b28f2abc966a386",
"src_ip": "6.19.128.119",
"dst_ip": "137.164.166.84"
},
]
}
A:
If this is a string representation of the object, first you need to set a variable and parse the string to have object you can work with.
jsonString = "{...your json string...}"
Then parse the string,
import json
jsonObject = json.loads(jsonString)
To access the data within it's like any other js object. Example :
jsonObject.tickets[0].timestamp
would return "2016/05/26 04:47:02"
tickets is the key within the jsonObject, 0 is the index of the first object in the list of tickets.
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Q:
Crystal Reports XI and MySQL Stored Procedure with Parameters
I am having a problem with a Crystal Report that displays data from a MySQL table. I am currently gathering the data directly from the table, however when the users try to input parameters, problems arise such as:
null values for parameters returning errors
parameters not working as specified
I then created a stored procedure to return data if a parameter is empty and will make the MySQL server do the work rather than the Crystal Reports server.
However Crystal Reports doesn't appear to recognize this and I am having some trouble displaying the results of the procedure.
Here is a copy of the procedure i am using:
Create Procedure sp_report
(IN @param1 varchar(64),
IN @param2 varchar(64),
IN @param3 int )
Begin
IF @param1 is null AND @param2 is null AND @param3 is null Then
Select * from tblData
ELSE IF @param1 is null AND @param2 is not null AND @param3 is not null then
Select * from tblData where field3 = @param3 and field2 = @param2
ELSE IF @param1 is not null AND @param2 is not null AND @param3 is null then
Select * from tblData where field2 = @param2 and field1 = @param1
ELSE IF @param1 is not null AND @param2 is null AND @param3 is not null then
Select * from tblData where field3 = @param3 and field1 = @param1
ELSE IF @param1 is not null AND @param2 is null AND @param3 is null then
Select * from tblData where field1 = @param1
ELSE IF @param1 is null AND @param2 is not null AND @param3 is null then
Select * from tblData where field2 = @param2
ELSE IF @param1 is null AND @param2 is null AND @param3 is not null then
Select * from tblData where field3 = @param3
ELSE IF @param1 is not null AND @param2 is not null AND @param3 is not null then
Select * from tblData where field3 = @param3 and field2 = @param2 and field1 = @param1
END;
Is there an easier way to do this or am I doing something wrong? Any suggestions would be greatly appreciated.
A:
If I'm reading your IF tree correctly, I think you could do this instead (I'm a T-SQL guy, so I can't confirm if this will run in MySQL):
SELECT *
FROM tblData
WHERE ((field1=@param1) OR (@param1 is null))
AND ((field2=@param2) OR (@param2 is null))
AND ((field3=@param3) OR (@param3 is null))
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Zeroing In On The Right Web Programming Language
The rapid development of Internet usage and varied necessity of the customers have motivated the web site designers and developers turning to numerous web programming languages. Nowadays, the veteran web-developers use several web programming language to help make the sites more functional and focus on the necessity of the customers who rely on the net for a number of reasons. However, the range of the server-side programming languages makes things harder for that web-developers too. They might fight to choose the best web programming language to build up their sites in the perfect way. The truth that the web site designers have to pack in multiple benefits inside a website makes adhering to particular programming language tough.
Ought to be fact, the accessible web programming languages could be classified into two groups- proprietary languages and Open-source languages. Each group has its own devoted fans worldwide. A budding website developer searching to find the best web programming language must understand the very fact there might be no perfect programming language for web development. Every programming language features its own talents and weak points along with a webmaster needs to choose which one fits his needs the very best.
Before homing in on the web programming language an internet site developer must think about some aspects. When the webmaster is focusing on a wide open source platform like Linux it might be achievable for him to choose a Free server side scripting language for adding functionality towards the websites. It must also be stored in your mind the Free web programming languages offer lower running costs. Yesteryear experience with an internet developer should be taken into consideration before selecting a web programming language. For instance, when the webmaster has background within an Object oriented programming language he should ideally select a web programming language that’s similar in structure. Outdoors source web programming languages have 1000’s of fans and also the designers may benefit so much from the internet forums and towns devoted to those languages.
Selecting a web programming language that’s platform independent can be quite useful for that website designers and the like a language will help with maintaining your development cycle flexible. Numerous website designers focusing on an internet site together can pick Java, a language that is platform independent. For the reason that situation they are able to share codes and collaborate regardless of the OS and platform they will use.
The web programming languages which are commercial items have a fee for certification. Like a webmaster, you need to turn out the cash for that product however in turn you receive robust support and integration along with other items provided by the organization, which, certainly is definitely an advantage. An industrial solution for web design is fantastic for the businesses getting enough resource and financial means searching forward to setup websites fast.
The web-developers have to think about the kind of websites that they will develop before choosing the right web programming language. If they will concentrate on making database driven websites then it seems sensible to select a scripting language that provides tight integration and compatibility with top after sales database application applications. Similarly, an internet site that requires frequent upgrading ought to be developed utilizing a flexible programming language that may be modified easily and it is lacking of complexity. |
A different set of 'star-crossed' Shakespearean lovers
Published 5:00 pm, Tuesday, June 9, 2015
Katie Wieland with Oliver Lehne in rehearsal for the Shakespeare on the Sound production of ìAllís Well That Ends Wellî running through June 28 in Pinkney Park in the Rowayton section of Norwalk.
Katie Wieland with Oliver Lehne in rehearsal for the Shakespeare on the Sound production of ìAllís Well That Ends Wellî running through June 28 in Pinkney Park in the Rowayton section of Norwalk.
Photo: Contributed Photo
A different set of 'star-crossed' Shakespearean lovers
1 / 1
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"All's Well That Ends Well" isn't high up on the list of Shakespeare's greatest hits.
Almost everyone has seen a production of "Romeo and Juliet" or "A Midsummer Night's Dream" at some point in their theatergoing lives, but "AWTEW" is rarely performed by the state's summer outdoor companies.
Norwalk's Shakespeare on the Sound is changing that with a new production running through Sunday, June 28.
Director Mary Robinson thinks audiences will share her love for the play.
"The characters are so wonderfully drawn and so rich and complicated. It's a relationship play that Shakespeare wrote at the top of his game, right around the time of `Hamlet,' " she said during a recent rehearsal break.
The play's heroine, Helena, is in love with Bertram, but faces that timeless trauma of realizing that he is just not that into her.
Katie Wieland, who is playing Helena, is described by Robinson as "the ideal Shakespeare heroine. She combines strength and vulnerability and has great depth. She also has a natural way with Shakespeare's language."
The director cast the two leading roles younger than might be standard in a "AWTEW" production to heighten the romantic dilemma at the center of the story.
"The tricky thing with Helena is the question: Why does she keep pursuing this man? I think casting young makes it really believable," she said.
With Shakespeare, in particular, you want performers who embody their characters so that the playwright's sometimes complicated plotting becomes lucid, she said.
This is the first time the veteran director has staged Shakespeare outdoors, which she believes adds another layer to his plays.
"There's something really special about seeing a play -- and listening to the verse -- under the stars," Robinson said.
"(Stratford) was such a special place and they used to pack that theater with 1,000 people at every show. When the theater closed, it left a real hole in the community, and now these smaller companies have been trying to fill that hole," she said.
Clarity is essential in Shakespeare and Robinson said she has called on "a terrific text coach" who spent the first 10 days of rehearsal going over the script with the actors.
"We've trimmed it a bit, too, down to two-and-a-half hours," the director said. "The goal is to make everything very clear." |
// Distributed under the terms of the MIT license
// Test case submitted to project by https://github.com/practicalswift (practicalswift)
// Test case found by fuzzing
class A{
protocol c{
typealias A:A
{
}
func b
protocol P{
class A{
{
{
}
}deinit{
if a{
{
deinit{
class a{
{
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:A" |
You are here
Underwater electric field receiver and emitter
This device is capable of emitting and receiving electic field underwater, in fresh and sea (salt) water. The technology is used multiple reconfigurable dipoles for emitting and sensing channels, extremelly low-noise amplifiers with adjustable filters, high-performance embedded microcontrollers for data pre-processing. Device is connected with standard PC/laptop via USB for further data processing and control.
Main features:
Receiver part
high sensitivity of sensing channels, in range on nV/m
voltage mode sensing and current mode sensing
excellent signal/noise relation due to a high-resolution ADC and extremely low-noise amplifiers
capability of data fusion from several sensing electrodes
capability to store the received signals in internal memory or to send to external PC/laptop
adjustable distance between receiving electrodes
adjustable number of receiving electrodes
purpose-specific geometrical form/shape of electrodes
Emitter part
programmable voltage output and DC offsets, -25 ... +25 Volts
current limiter for each dipole
high-resolution DAC for signal generation
capability of playing/generating arbitrary waveforms/signals
capability of emitting a stored signal from internal memory
adjustable distance between emitting electrodes
adjustable number of emitting electrodes
purpose-specific geometrical form/shape of electrodes
Application areas
This device can be produced in stationary or mobile versions and scalable in size of application: from laboratory experiments in small- and middle-size aquariums up to open-water applications.
performing biological experiments with electric fishes, parameters of emitting/receiving electronics can be adjusted to specific fish species |
Heroldo de Esperanto
Heroldo de Esperanto () is a magazine published in Esperanto. It was founded in 1920 by Teo Jung in Cologne under the name of Esperanto triumfonta and was edited by Jung from 1920 to 1961.
In the years before the Second World War it appeared on a weekly basis. It survived until 1936, when it was closed down by the German Nazi Party authorities and its presses were confiscated.
Jung and his wife left Germany for the Netherlands, where he began publishing again. After a break during the war, the paper again appeared, but this time was published fortnightly.
The editorship was held by Ada Fighiera Sikorska from 1962 until 1996. In 1966 the paper was sold to LF-koop in Switzerland and the editorship was undertaken by Perla Martinelli until the publication of issue no. 2000. Stano Marček then edited it for 2 years.
Under the ownership of LF-koop it has become independent of the traditional Esperanto movement. At present it is edited by a multinational editorial committee and appears on a three-weekly basis. The content is overwhelmingly concerned with the activities of the Esperanto movement.
In June 2016 the paper was sold to Lexus publishing house in Brazil, whose editorship will begin in January 2017; but only one number was published after December 2016.
A newsletter called Heroldo, a monthly publication of Kultura Centro Esperantista (Esperanto Cultural Centre), but also discussing wider issue of the Esperanto-speaking community, is published regularly in Switzerland.
External links
Heroldo de Esperanto
Category:1920 establishments in Germany
Category:Esperanto magazines
Category:German magazines
Category:Magazines established in 1920
Category:Media in Cologne
Category:German weekly magazines
Category:Biweekly magazines
Category:Esperanto in Germany |
Intrepid shoppers have found a loophole to skirt Costco's membership fees.
Costco, a membership-based wholesale retailer, offers discounts for consumers willing to pay an annual fee, which ranges from $55 to $110.
But customers can avoid those fees by paying with a gift card. Only members can purchase the cards, but anyone can use them.
A quick online search turns up blogs and websites that encourage customers to avoid membership fees by using gift cards instead.
Patrons who pay for a membership, like Scott Cowie, say this seems unfair.
Some Costco shoppers are paying for their purchases with gift cards to avoid annual membership fees. (Rick Bowmer/Associated Press)
"It sounds a bit annoying that I have to pay a membership to Costco and people can just give gift cards and give them to anyone they want without an extra fee being applied," said Cowie.
Cowie thinks the loophole could be abused. He thinks members could charge a small fee in exchange for purchasing the cards for non-members.
A Costco representative told the CBC that people rarely take advantage of the gift card system. If it is, the representative said, the company addresses it.
Consumer advocate Anna Wallner suspects the loophole might not last for much longer.
"I think people will always be looking for the advantage, but eventually if people are taking advantage of the system then I'm sure at some point Costco or whoever the retailer is will change the system," says Wallner.
Wallner says consumers who try to save a few dollars by getting friends or family to buy them Costco gift cards may want to reconsider.
"If you're spending a whole lot of time getting other people to buy gift cards for you, then you need to consider what your time is worth," says Wallner. |
Opinion
Last Friday, HR-2454 passed the house by a narrow vote. Obama and Pelosi got their way. The American Clean Energy Act of 2009 (cap and trade) is another step closer to being law. Only the U.S. Senate stands between us and an economic meltdown. Th...
Congress is considering legislation called the Employee Free Choice Act. If passed, the Act would make it easier for people to join labor unions and bargain for higher wages and better benefits. This, in turn, would provide some much-needed sti... |
Q:
Authlogic OpenID integration
I'm having difficulty getting OpenId authentication working with Authlogic. It appears that the problem arose with changes to the open_id_authentication plugin. From what I've read so far, one needs to switch from using gems to using plugins.
Here's what I done thus far to get Authlogic-OpenID integration working:
Removed relevant gems:
authlogic
authlogic-oid
rack-openid
ruby-openid *
Installed, configured, and started the authlogic sample application (http://github.com/binarylogic/authlogic_example)--works as expected. This required:
installing the authlogic (2.1.3) gem ($ sudo gem install authlogic)
adding a dependency (config.gem "authlogic") to the environment.rb file.
added migration to add open-id support to User model; ran migration; columns added as expected
made changes to the UsersController and UserSessionsController to use blocks to save each.
made changes to new user-sessions view to support open id (f.text_field :openid_identifier)
installed open_id_authentication plugin ($ script/plugin install git://github.com/rails/open_id_authentication.git)
installed the authlogic-oid plugin ($ script/plugin install git://github.com/binarylogic/authlogic_openid.git)
installed the plugin ($ script/plugin install git://github.com/glebm/ruby-openid.git)
restarted mongrel (CTRL-C; $ script/server)
Mogrel failed to start, returning the following error:
/Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `gem_original_require': no such file to load -- rack/openid (MissingSourceFile)
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:521:in `new_constants_in'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/plugins/open_id_authentication/lib/open_id_authentication.rb:3
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `gem_original_require'
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:521:in `new_constants_in'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/plugins/open_id_authentication/init.rb:5:in `evaluate_init_rb'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin.rb:146:in `evaluate_init_rb'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/core_ext/kernel/reporting.rb:11:in `silence_warnings'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin.rb:142:in `evaluate_init_rb'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin.rb:48:in `load'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin/loader.rb:38:in `load_plugins'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin/loader.rb:37:in `each'
from ./script/../config/../vendor/rails/railties/lib/rails/plugin/loader.rb:37:in `load_plugins'
from ./script/../config/../vendor/rails/railties/lib/initializer.rb:348:in `load_plugins'
from ./script/../config/../vendor/rails/railties/lib/initializer.rb:163:in `process'
from ./script/../config/../vendor/rails/railties/lib/initializer.rb:113:in `send'
from ./script/../config/../vendor/rails/railties/lib/initializer.rb:113:in `run'
from /Users/craibuc/NetBeansProjects/authlogic_example/config/environment.rb:13
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `gem_original_require'
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:521:in `new_constants_in'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/activesupport/lib/active_support/dependencies.rb:156:in `require'
from /Users/craibuc/NetBeansProjects/authlogic_example/vendor/rails/railties/lib/commands/server.rb:84
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `gem_original_require'
from /Library/Ruby/Site/1.8/rubygems/custom_require.rb:31:in `require'
from script/server:3
I suspect this is related the rack-openid gem, but as it was dependent upon the ruby-openid gem, it was removed when the ruby-openid gem was removed. Perhaps this can be installed as a plugin.
Any assistance with this matter is greatly appreciated--I'm just about to give up on OpenId integration.
* ruby-openid (2.1.2) is installed at /System/Library/Frameworks/Ruby.framework/Versions/1.8/usr/lib/ruby/gems/1.8. I'm not certain if this is affecting anything. In any case, I'm not sure how to uninstall it or if I should.
** edit **
It appears that there are a number of gems in the /Library/Ruby/Gems/1.8/gems directory that may be causing an issue:
authlogic-oid (1.0.4)
rack-openid (1.0.3)
ruby-openid (2.1.7)
Questions:
- why doesn't the gem list command list these gems?
- Why doesn't the gem uninstall command remove these gems?
A:
i've got the same problem here just now, but fixed just installing the rack-openid gem.
I'll ask them to add rack-openid to the required libraries on documentation
A:
I went through the same hassles as you did.
Maybe you should just check this out, have got everything working:
http://github.com/shripadk/authlogic_openid_selector_example
This includes a stackoverflow like openid autoregistration too. I have hosted an example app on heroku for you to try out before checkout if you want to.
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import { Observable } from 'rxjs/Observable'
import { ScenarioFieldConfigId } from 'teambition-types'
import { SDK } from '../../SDK'
import { SDKFetch } from '../../SDKFetch'
import { ScenarioFieldConfigSchema } from '../../schemas'
export function restoreScenarioFieldConfigFetch(
this: SDKFetch,
scenarioFieldConfigId: ScenarioFieldConfigId
): Observable<ScenarioFieldConfigSchema> {
return this.put(
`scenariofieldconfigs/${scenarioFieldConfigId}/restore`
)
}
export function syncScenarioFieldConfigFetch(
this: SDKFetch,
scenarioFieldConfigId: ScenarioFieldConfigId
): Observable<{}> {
return this.put(
`scenariofieldconfigs/${scenarioFieldConfigId}/sync`
)
}
declare module '../../SDKFetch' {
interface SDKFetch {
restoreScenarioFieldConfig: typeof restoreScenarioFieldConfigFetch
syncScenarioFieldConfig: typeof syncScenarioFieldConfigFetch
}
}
SDKFetch.prototype.restoreScenarioFieldConfig = restoreScenarioFieldConfigFetch
SDKFetch.prototype.syncScenarioFieldConfig = syncScenarioFieldConfigFetch
export function restoreScenarioFieldConfig(
this: SDK,
scenarioFieldConfigId: ScenarioFieldConfigId
) {
return this.lift({
tableName: 'ScenarioFieldConfig',
method: 'update',
request: this.fetch.restoreScenarioFieldConfig(
scenarioFieldConfigId
),
clause: { _id: scenarioFieldConfigId }
})
}
export function syncScenarioFieldConfig(
this: SDK,
scenarioFieldConfigId: ScenarioFieldConfigId
) {
return this.lift({
tableName: 'ScenarioFieldConfig',
method: 'update',
request: this.fetch.syncScenarioFieldConfig(
scenarioFieldConfigId
).map(() => ({ _id: scenarioFieldConfigId })),
clause: {}
})
}
declare module '../../SDK' {
interface SDK {
restoreScenarioFieldConfig: typeof restoreScenarioFieldConfig
syncScenarioFieldConfig: typeof syncScenarioFieldConfig
}
}
SDK.prototype.restoreScenarioFieldConfig = restoreScenarioFieldConfig
SDK.prototype.syncScenarioFieldConfig = syncScenarioFieldConfig
|
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|
A. The POTS Network
The Plain Old Telephone Service (POTS) network, which has been in existence for over 100 years, is well designed and well engineered for the transmission and switching of 3 kHz voice calls. The POTS network is a real-time, low-latency, high reliability, moderate fidelity voice telephony network. It is not designed for, nor especially well suited for, other forms of communications, including wideband speech or audio, images, video, fax, and data. The POTS network is inherently “telephone” or “handset” oriented and is driven by the need of real-time voice telephony.
There are approximately 270 million users of the POTS network in the United States, making POTS access nearly ubiquitous throughout the US. On the other hand, the POTS network has high access costs, and for international calls, settlement costs.
1. Voice and Signaling Circuits
Today's POTS network includes a plurality of subnetworks. The two primary subnetworks are a circuit-switched voice subnetwork and an out-of-band signaling subnetwork. In addition, the POTS network includes other packet subnetworks used for operations and network management functions.
The POTS circuit-switched voice subnetwork includes voice-grade circuits that can carry voice signals or data at multiples of a basic 64 kilobits/second rate. The voice subnetwork includes a multiplicity of Service Switching Points (SSP) that are used to set up circuit-switched connections that carry voice traffic or data traffic (i.e., the “payload”) on the POTS network. Each SSP may be a switch used by a Local Exchange Carrier (LEC), such as a 5ESS® switch (5E) made by Lucent, or a switch used by an InterExchange Carrier (IXC), such as a 4ESS® switch (4E) made by Lucent.
The POTS signaling subnetwork is itself a packet-switched network, denoted as Signaling System 7 (SS7). The SS7 signaling subnetwork carries digital information which assists in fast call setup and routing, as well as providing transaction capabilities using remote database interaction. The SS7 signaling subnetwork includes a series of paired components connected to an SSP. Typically, each of the paired components for the SS7 signaling subnetwork includes one or more Signal Transfer Points (STP) and one or more Service Control Points (SCP). Each STP and SCP provides, respectively, a router and a database used to implement call setup, call routing, call control and the logic (or programs) and related information functions used to provide advanced communications services over the POTS network. Details of STPs and SCPs, their operation, and how they interact with SSPs are well-understood by those skilled in the art.
The SS7 signaling subnetwork also includes a protocol (which, in turn, includes a series of sub-protocols). Thus, for example, under the SS7 protocol, it is possible to automatically transfer information about the calling party to the called party (i.e., the so-called “Caller ID”). Furthermore, e.g., the SS7 signaling subnetwork and protocol interacts with the voice subnetwork so as to enable a query from an SSP in the voice subnetwork to a Service Control Point (SCP) database in the SS7 subnetwork for determining how to route a call, such as a toll-free (e.g., “800“1) call. Thus, e.g., the SCP can return to the SSP a routing number corresponding to the dialed “800” number. Additional call features or services utilizing the interaction capabilities of the voice and signaling subnetwork of the POTS network are well known.
2. Interactive Voice Response Systems
Using known interactive voice response (IVR) techniques, callers can directly update database records or select specific information for retrieval by, e.g., entering touch-tones or using voice commands. Retrieved textual information can be converted to speech and played over the phone, or sent directly to the caller as a fax document. As a result, customers can access information or place orders at their convenience without waiting for a service representative. Businesses benefit by reducing costs associated with attendants and service representatives and by increasing customer satisfaction.
B. Packet Networks
Packet networks are general-purpose data networks which are not tied to fixed-bandwidth circuits. Instead, they are designed to transmit bits (in the form of a packet of fixed or variable length) only when there are bits to transmit. Packet networks evolved independently of telephone networks for the purpose of moving bursty, non-real-time data among computers and are distinguished by the property that packet communications are routed by address information contained in the data stream itself.
Packet networks are especially well suited for sending stored data of various types, including messages, fax, speech, audio, video and still images, but are not well suited for sending real-time communication signals such as real-time speech, audio, and video signals. Typically, one accesses a packet network through a client program executing on a personal computer (PC), and so packet networks are inherently “PC” oriented, and client/server driven. Packet networks provide access to distributed databases and have excellent search capabilities.
There are approximately 30 million users of packet networks in the US; this number of users is growing rapidly and will continue to do so over the next decade. Today, the Internet (the largest and most renowned of the existing packet networks) connects over 4 million computers in some 140 countries. The Internet is implemented using a large variety of connections between those millions of computers. These interconnected computers can support applications, such as electronic mail and the World Wide Web, which facilitate communications between persons across the U.S. or around the globe.
Among the connections between computers typically found on the Internet are routers. Routers serve to send packets along to their destination by examining packet headers to determine the destination address; routers often send packets to another router closer to the destination.
Access to the Internet may be obtained through a point of presence (POP), typically through a server connected to one of the networks that make up the Internet. A large company or business may establish a POP as its own direct connection to the Internet; individuals or small businesses may typically access the Internet through a service provider which may provide a POP for, potentially, a multitude of individuals and businesses.
The Internet's global and exponential growth is common knowledge today. The recent developments of browsers for World Wide Web interfaces and information navigation software, such as a multitude of Web search engines (such as, e.g., Lycos or Alta Vista), coupled with a continuously growing number of public access providers, are making the Internet a fundamental component of the information age, if not the information super highway itself. Users typically communicate over the Internet using a combination of hardware and software providing interconnectivity that is compatible with the standard, namely Transmission Control Protocol/Internet Protocol (TCP/IP).
Several alternate forms of communication have developed which utilize either the POTS network or packet networks (and sometimes both). For example, facsimile (fax) communication is now a commonplace option for transmitting copies of documents over the POTS network. Electronic messaging (e.g., e-mail) is a growing phenomenon for those who use a packet network, particularly the Internet, for communications. In addition, many companies today are using packet networks, locally or internally within the company, which are modeled in functionality based upon the Internet. These packet networks, denoted “intranets,” are typically private networks owned or controlled by the company or corporate user. Packets are moved over intranets using the Internet Protocol (IP), and often the same software used in connection with the Internet (e.g., Web browsers) is also used in connection with intranets. Intranet networks are often established to connect to the Internet through a firewall (i.e., a hardware/software combination designed to restrict unauthorized access to the intranet from the outside world).
As the Internet grows, more organizations are publishing information on a “site” on the World Wide Web (Web site). Furthermore, generally available and excellent search capabilities can locate a particular piece of information quickly from this globally-distributed database.
A World Wide Web site on the Internet typically resides on a computer known as a server, which is accessed through the Internet by a person (or a client) utilizing a computer, such as a PC. A Web site consists of one or more Web pages comprising scripts written in Hyper Text Markup Language (HTML) and typically resides on a server compatible with HyperText Transport Protocol (HTTP, a protocol for interfacing with the Internet). Pages at a Web site are typically accessible and viewed by the person using the PC through software called a Web browser, which typically resides on the person's PC. A Web browser, such as the one by Netscape, interprets Web page HTML scripts to provide a graphical user interface that allows easy access to various services over the Internet. Equivalently, Web sites internal to and locatable over a corporate intranet may be set up and accessed in a like manner using the same or virtually the same software (e.g., a Web browser). Such Web sites internal to a corporate intranet are typically HTTP compatible and addressable using Uniform Resource Locator (URL) techniques, and contain Web pages comprising HTML scripts.
Persons may browse the World Wide Web for virtually any kind of information, including information having content derived from one or more media, such as words, sounds or images. Increasingly, businesses are establishing Web sites as a means of providing information to and attracting potential customers, and Web sites are emerging as a means of transacting business. One may locate a company's Web site by, e.g., using one of a number of existing search engines available over the Internet, or browsing other Web sites containing links to the company's Web site, or entering directly the URL, which represents an address for the Web site. Typically, Web browsing takes place in the context of an interactive communication session, where one may, for example, direct the Web browsing session by choosing to follow hypertext links found in Web sites and/or may respond to information located at various Web sites.
C. Integration of the POTS and Packet Networks
Recently, several new evolutionary systems have emerged with the goal of integrating the POTS and packet networks, including the introduction of packet telephony and “hop-on hop-off” servers.
1. Packet Telephony
An Internet-related development is packet telephony. Packet telephony involves the use of a packet network, such as the Internet, for telecommunicating voice, pictures, moving images and multimedia (e.g., voice and pictures) content. Instead of a pair of telephones connected by switched telephone lines, however, packet telephony typically involves the use of a “packet phone” or “Internet phone” at one or both ends of the telephony link, with the information transferred over a packet network using packet switching and packet routing techniques.
Packet telephony systems were created with the goal of providing real-time speech communications over packet networks. The basic idea of packet telephony is (1) to use the sound board of a multimedia PC to digitize speech into bits; and (2) to use the processor in the computer to compress the bitstream, packetize it, and then send the result over a packet network to another multimedia PC with the same or equivalent functionality. Although the basic idea is feasible, the resulting real-time voice communications experience is of low quality, albeit at low cost. Some of the drawbacks are: long transmission delays (due to packet size, packet buffering, packet overheads and routing delays) lost and delayed packets (due to network congestion) poor quality of the coded voice (due to the use of low complexity speech coders) difficulty of finding the Internet Protocol (IP) address of the person at the destination need to call people who did not have access to the packet networkSeveral improvements in these areas have been made since the initial introduction of packet telephony, and others have been suggested (e.g., reservation protocols such as RSVP).
2. HOHO Servers
As packet telephony grew in popularity, the need to call people who did not have access to the packet network led to the creation of Hop-on Hop-Off (HOHO) servers. The development of Hop-on Hop-Off servers provided a mechanism for PC-initiated telephone calls on a packet network to connect with the POTS network and terminate at a customer's telephone handset or vice-versa. The HOHO or server brings the packet network and POTS network together at a common gateway interface, which bi-directionally converts IP packets into voice and signaling information, such as the sequence of messages used to set up, bridge, and tear down calls. In this way, voice communication is established across the packet and POTS networks.
3. Call Center-Based Telephony
Another recent development in linking together the POTS and packet networks is the call center-based system developed by Genesys Telecommunications Laboratories, among others. In a typical call center-based scenario, a customer finds a product/service, while browsing the Web, for which more information is desired. If the particular product/service provider maintains both a Web server and a call center, the customer, along with the Web connection, can be linked to a call center representative in the following way. The customer is asked to click on a button on the PC screen which requests customer information (e.g. home telephone number, name, etc.). The Web server passes the information to the database server in the call center system, which initiates a POTS call to the customer and connects the call to a call center representative. At the same time, the Web page that the customer is looking at may be passed to the call center representative, along with side information such as the length of time that the customer has been looking at the page, the previous pages which have been looked at, etc. In this manner, the customer maintains a voice connection to the call center representative, as well as synchronization between what the call center representative sees on the PC screen and what the customer sees on the PC screen.
While the systems described above provide some limited usefulness for individualized applications, none of these systems provide a comprehensive means for combining the POTS network and a packet network (such as the Internet) in a way that takes full advantage of the signaling and real-time signal processing capabilities present in the POTS network. For example, current packet telephony systems do not take advantage of the SS7 signaling subnetwork and protocols to assist call setup and routing. Further, none of the current systems that enable packet telephony using a POTS telephone connection at one or both ends have the capability to intelligently make switching or routing decisions between the POTS network and packet network based upon considerations such as desired quality, time, cost, bandwidth or other considerations.
What is desired is a way to combine the POTS network and a packet network, taking full advantage of the signaling capabilities present in the POTS network as well as the addressing capabilities inherent in a packet network, to seamlessly combine the networks for flexible and optimal communications based upon considerations such as desired quality, time, cost or bandwidth. |
Former enemies Imam Dr Muhammad Ashafa and Pastor Dr James Wuye spent years as the leaders of violent militias fighting each other in Nigeria, but an unlikely coming together saw their worlds come together in emphatic fashion and they are now best friends. The religious leaders have been in New Zealand to meet Muslim community and other community leaders in Christchurch and speak at events in Wellington and Auckland. |
After multiple failed attempts to sabotage the Trump Presidency, Democrats have decided that impeachment is the only way they stand a chance at taking back the White House. The party of futile resistance thought they had found a way to take down the President, but after only 24 hours their narrative fell apart.
Speaker of the House Nancy Pelosi succumbed to pressure from the radical wing of her party and opened an official impeachment inquiry. This move was based nearly entirely off of uncorroborated reports that the President pressured Ukrainian President Zelensky into opening an investigation into Joe and Hunter Biden. In announcing the proceedings, Pelosi alluded to this by falsely claiming that the President had committed a “betrayal of his oath of office.”
Democrats eagerly marched forward with their impeachment narrative, until the next morning when the Trump administration released transcripts of the President’s conversation with the Ukrainian President. The transcripts completely dismantled the Democrats’ narrative that a “quid-pro-quo” was established.
Following the release of the transcripts, President Trump and President Zelensky also took questions from the media, during which the Ukrainian President stated firmly, “Nobody pushed me” to open an investigation into Joe and Hunter Biden.
Just like that, within hours of Pelosi announcing an official impeachment inquiry, the Democrats’ impeachment narrative had completely fallen apart.
But, the media frenzy didn’t stop there. While Democrats were still pushing their entirely debunked impeachment narrative, media reports surfaced that alleged the whistleblower, who started this whole inquiry, was actually a CIA Officer attached to the White House. Not only that, but the rules for submitting a whistleblower complaint were, reportedly, secretly changed prior to the filing of the report. And, after the change, there was no longer a requirement of firsthand knowledge of a crime being committed.
So, the Democrats’ entire impeachment narrative was started by a complaint from a “whistleblower” who had no direct knowledge of the alleged incident that both Presidents firmly denied, and the transcript thoroughly debunks.
Leaving the American people with the question, where did the whistleblower report come from? And why was it filed in the first place?
Former CIA Analyst Fred Fleitz attempted to answer this question, addressing the many factors that seemed to indicate that “the author had a lot of help,” and typically this help is derived from members of the House Intelligence Committee. This makes the timing of the complaint look less like a coincidence, and more like a targeted political move. According to Fleitz, the complaint was “too convenient and too perfect to come from a typical whistleblower.”
All the evidence is beginning to point to what Republicans have suggested since the beginning of this entire story. Not only is the inquiry based off of another salacious and unverified document, this attempted impeachment process is nothing short of a political coup orchestrated by the Democratic establishment. When they know they can’t beat the President in 2020, they attempt to impeach him with no evidence of any wrongdoing whatsoever. And even if the impeachment proceedings fail, which they will, Democrats’ secondary goal is to tarnish his reputation, in a Hail Mary attempt to make him politically ineffective.
This move is nothing more than a show of complete desperation, and it won’t work. President Trump’s poll numbers continue to rise, the Trump Campaign continues to receive more donations, and the President is continuing his work to Make America Great Again. |
1. Field of the Invention
The present invention relates to a liquid crystal display and a back light to be arranged behind a liquid crystal panel in the liquid crystal display.
2. Description of the Related Art
Generally, liquid crystal displays have a liquid crystal panel and a back light for irradiating the backside of the liquid crystal panel with light. In recent years, liquid crystal displays have improved and approached CRTs (Cathode Ray Tubes) in terms of performance. Liquid crystal displays thus have found an increasing range of applications, including navigation systems to be mounted on motor vehicles.
In motor vehicles, the interior brightness varies greatly between daytime and nighttime hours. Cars are dark inside in the nighttime, so that cars' navigation systems must be lowered sufficiently in screen brightness in the nighttime. That is, liquid crystal displays for use in the navigation systems need to have a smaller minimum luminance for the sake of nighttime use.
FIG. 1 shows a block diagram of a control circuit in a back light 10 to be used for this type of liquid crystal display. In the diagram, the back light 10 includes an oscillating circuit 12, lighting circuits 14a, 14b, and 14c, a light volume adjusting circuit 16, and fluorescent tubes 18a, 18b, and 18c.
The light volume adjusting circuit 16 receives brightness adjusting input which is generated in accordance with a luminance adjusting signal from exterior, and outputs, to the oscillating circuit 12, a light volume adjusting signal for adjusting the fluorescent tubes 18a, 18b, and 18c in brightness. The oscillating circuit 12 generates an alternating voltage corresponding to the light volume adjusting signal out of the power supplied from a power source, and outputs the generated alternating voltage to the lighting circuits 14a, 14b, and 14c. The lighting circuits 14a, 14b, and 14c boost the alternating voltage output from the oscillating circuit 12, and supply the boosted voltages to the fluorescent tubes 18a, 18b, and 18c. The fluorescent tubes 18a, 18b, and 18c light up at luminances corresponding to the voltage waveforms supplied.
FIG. 2 shows an overview of structure of a light emitting part 10a in the back light 10. The light emitting part 10a has a reflector 20 for accommodating the fluorescent tubes 18a, 18b, and 18c.
The inner surface of the reflector 20 is given a reflecting coat of metal. The fluorescent tubes 18a, 18b, and 18c are arranged in parallel inside the reflector 20. The light emitted from the fluorescent tubes 18a, 18b, and 18c radiates out directly or after reflected from the inner surface of the reflector 20.
In the back light 10 shown in FIG. 1, the single light volume adjusting circuit 16 adjusts the plurality of fluorescent tubes 18a, 18b, and 18c in luminance. On this account, when the back light 10 produces an output of the minimum luminance, the fluorescent tubes 18a, 18b, and 18c are lit at their respective minimum luminances. Consequently, the minimum luminance possible for the back light 10 to output is the sum of the minimum luminances of the individual fluorescent tubes 18a, 18b, and 18c. When liquid crystal displays having such a back light are applied to the navigation systems, the screen brightness cannot be lowered to an appropriate brightness in nighttime use.
According to the structure of the light emitting part 10a of the back light 10 shown in FIG. 2, the central fluorescent tube 18b faces a smaller area of the reflector 20 and the outer fluorescent tubes 18a and 18b face greater areas of the reflector 20. The parasitic capacitance occurring between the fluorescent tube 18b and the reflector 20 is therefore smaller than the parasitic capacitance occurring between the fluorescent tube 18a and the reflector 20, and the parasitic capacitance occurring between the fluorescent tube 18c and the reflector 20.
Therefore, the current to flow through the fluorescent tube 18b is greater than the currents to flow the fluorescent tubes 18a and 18c. This shortens the life of the fluorescent tube 18b more than the lives of the fluorescent tubes 18a and 18c. In general, fluorescent tubes of a back light cannot be replaced separately. Thus, the entire back light must be replaced when any one of the fluorescent tubes no longer works. That is, the life of a back light becomes shorter depending on the fluorescent tube of the shortest life.
Recently, parts of the liquid crystal displays tend to get smaller in size due to a growing demand for liquid crystal panels of larger size. The reflectors accommodating the fluorescent tubes of the back lights also have the inclination to shrink in size. This results in reducing interior spaces of the reflectors and easy trapping of heat within the reflectors. Consequently, if a plurality of fluorescent tubes is used, there is a possibility that concentrate generated heat therein may hamper sufficient heat dissipation. |
The diagnosis and treatment challenges in nosocomial pneumonia.
Pneumonia is the second most common type of nosocomial infection and is most prevalent in patients who are mechanically ventilated. Nosocomial pneumonia (NP) is the leading contributor to mortality in patients, accounting for approximately 50% of deaths in patients with hospital-acquired infections. Several factors place patients at risk for developing NP, including prolonged length of hospital stay and local epidemiology. Gram-positive pathogens such as Streptococcus pneumoniae and, more recently, Staphylococcus aureus, as well as atypical organisms such as Legionella spp are increasingly associated with NP. Emerging antimicrobial resistance among these organisms confounds treatment interventions. Lack of local definitive information and patient comorbidities further complicate the physician's treatment decisions. The role of invasive pulmonary diagnostic techniques remains problematic and controversial. Studies, however, have shown that early initiation of appropriate empiric therapy is essential to improving patient outcome and reducing mortality. This article will review therapeutic options and appropriate antimicrobial agents for use in the treatment of nosocomial pneumonia in the era of emerging drug resistances. |
Chris Petersen, a North Carolina mail carrier, wanted to be home with his family the night before Christmas but was running late on his route. His timing, however, became a Christmas miracle.
Petersen was on his regular route in Cary, a town about 10 miles west of Raleigh, when he helped save someone’s life.
He had just delivered mail to a home when, moments later, he heard Pam Hodgin yell for help.
The 32-year U.S. Postal Service veteran and two other neighbors ran inside the home and the three immediately jumped into action.
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The trio found Mike Hodgin collapsed on the kitchen floor. He was not breathing. Petersen began performing CPR and, about two minutes later, Hodgin took a big breath and opened his eyes.
Petersen returned to his mail route as soon as emergency responders arrived.
“My mother-in-law always says that everything happens for a reason,” Petersen told Fox News. “I was running late that day because I was meant to be there to help Mike. I couldn’t have imagined a better outcome.”
Hodgin and Petersen reunited on New Year’s Day.
MICHIGAN 'MIRACLE LADY' STARTS BREATHING MOMENTS AFTER PLUG IS PULLED ON LIFE SUPPORT
“Chris is my hero and it is because of him I’m alive today to watch my grandsons grow and enjoy each new day,” Hodgin said as he held one of his grandsons.
Hodgin said he now plans to get certified on CPR so he too can help save a life. |
Rise & Shine: New hope for a historic lawsuit?
Remember last summer when a federal judge dismissed the big Detroit right-to-literacy lawsuit? A lot of folks thought it was dead.
But not Mark Rosenbaum. He’s the lead attorney who filed the lawsuit two years ago. Even then, Rosenbaum insisted this historic effort would continue to move forward. An appeal was filed. And this week, 15 briefs were filed in support of the plaintiff’s appeal.
I asked Rosenbaum Wednesday how he was feeling about the case.
“I’m 100% confident,” he said.
Read the story I posted yesterday about the new developments in the lawsuit — and the possibility that the arrival of a new governor in January could alter its fate.
Also, mark your calendars for next week’s second annual State of the Schools address where Superintendent Nikolai Vitti will share the stage with charter school leaders. Tickets for the event are free, but registration is required.
Scroll down for more headlines.
— Lori Higgins, Senior Reporter
Rise & Shine is Chalkbeat’s morning digest of education news. Subscribe to have it delivered to your inbox.
SUIT Governor-elect Gretchen Whitmer said she is reviewing the right-to-read suit to decide whether the state will continue its opposition. Chalkbeat
STATE OF THE SCHOOLS While last year’s first State of the Schools address led to fiery exchanges between district and charter school leaders, this year’s discussion could focus on how the two sectors are working together on a joint bus route and a citywide grading system. Chalkbeat
FAMILIAR New research finds that when students have “familiar faces” around them in class, they’re less likely to be chronically absent — yet another reason why students frequently changing schools in cities like Detroit is so concerning. Chalkbeat
PRIVATE FUNDING: A coalition of education and other advocacy groups is urging the state’s highest court to take up a lawsuit that challenges a relatively new state law that allows private schools to receive some state funding. Michigan RadioThe Detroit News
SAFE WATERThree Michigan academics question why Detroit and Flint schools, which are using donations to pay for water hydration stations, are having to turn to private sources to fund public problems. Washington Post
RESEARCH Two state agencies and two universities have formed a new research institute with the goal of improving K-12 public schools across the state. MSU |
import logging
from gensim.models import LdaModel
from gensim import corpora
logging.basicConfig(format='%(asctime)s : %(levelname)s : %(message)s', level=logging.INFO)
dictionary_path = "models/dictionary.dict"
corpus_path = "models/corpus.lda-c"
lda_num_topics = 50
lda_model_path = "models/lda_model_50_topics.lda"
dictionary = corpora.Dictionary.load(dictionary_path)
corpus = corpora.BleiCorpus(corpus_path)
lda = LdaModel.load(lda_model_path)
for i, topic in enumerate(lda.show_topics(num_topics=lda_num_topics)):
print '#%i: %s' %(i, str(topic))
|
The arrests of illegal immigrants crossing the southwest border by Border Patrol agents decreased again in April. This is the fifth straight month of decline. The total apprehensions of illegal border crossers hit a 17-year low.
The April report, released this week, reveals that apprehensions dropped from the previous month by five percent. The number of apprehensions has dropped each month since President Donald Trump took office. In January, 42,473 illegal immigrants were apprehended after crossing the border. By April, that number had dropped to 15,780, a drop of 26,693.
U.S. Customs and Border Protection (CBP) spokesman David Lapan told NumbersUSA, “A lot of the discussion about changes in our enforcement policy and the way we are going about doing business, we believe that has deterred people. When you get here, it is likely you are going to get caught. You are going to be returned to your country.”
The discussions also appear to be deterring Unaccompanied Alien Children (UAC) and Family Unit Aliens (FMUA) from risking their lives to travel to the U.S. illegally. The arrest of UACs dropped from the January mark of 4,441 to April’s 998. April’s numbers were down from March by 45.
The arrest of FMUAs illegally crossing the border dropped from 9,300 in January to 1,119 in April. FMUA apprehensions in March were at 1,126.
The Rio Grande Valley Sector (RGV) in south Texas remains the hotspot for border apprehensions. Of the 29,608 UACs arrested in FY 2017, 18,313 were arrested in the RGV Sector. The next closest sector is El Paso, which accounted for 2,765 of the UAC arrests.
The same is true of FMUA apprehensions. FY2017 arrests totaled 59,510. Nearly 40,000 of those entered the U.S. in the RGV sector. The next closest sector, El Paso, reported 7,235 FMUAs apprehended in the first seven months of this fiscal year.
The largest number of UACs entering the U.S. illegally came from Guatemala (9,989). El Salvador sent 7.804 minors to the U.S. Border while Honduras and Mexico followed with 6,305 and 5,306 respectively. The largest number of FMUAs apprehended came from El Salvador (20967). Guatemala and Honduras followed closely with 17,555 and 17,542 respectively. Mexico trailed with only 1,603.
CBP officials define FMUA as “the number of individuals (either a child under 18 years old, parent or legal guardian) apprehended with a family member by the U.S. Border Patrol.)”
Center for Immigration Studies Director of Policy Studies Jessica Vaughan told NumbersUSA “The continued drop suggests this is more than just a fluke.”
Bob Price serves as associate editor and senior political news contributor for Breitbart Texas. He is a founding member of the Breitbart Texas team. Follow him on Twitter @BobPriceBBTX and Facebook. |
#ifndef __WON_ROUTINGGROUPFLAGSCHANGEDOP_H__
#define __WON_ROUTINGGROUPFLAGSCHANGEDOP_H__
#include "WONShared.h"
#include "RoutingOp.h"
#include <string>
namespace WONAPI
{
///////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////
class RoutingGroupFlagsChangedOp : public RoutingOp
{
private:
unsigned short mGroupId;
unsigned long mNewGroupFlags;
unsigned long mNewAsyncFlags;
virtual WONStatus HandleReply(unsigned char theMsgType, ReadBuffer &theMsg);
public:
RoutingGroupFlagsChangedOp(RoutingConnection *theConnection) : RoutingOp(theConnection) {}
unsigned short GetGroupId() const { return mGroupId; }
unsigned long GetNewGroupFlags() const { return mNewGroupFlags; }
unsigned long GetNewAsyncFlags() const { return mNewAsyncFlags; }
bool GetIsClaimed() const { return (mNewGroupFlags & RoutingGroupFlag_Claimed) != 0; }
bool GetIsClosed() const { return (mNewGroupFlags & RoutingGroupFlag_Closed) != 0; }
bool GetIsPasswordProtected() const { return (mNewGroupFlags & RoutingGroupFlag_PasswordProtected) != 0; }
bool GetAllowOutsidersToChat() const { return (mNewGroupFlags & RoutingGroupFlag_AllowOutsidersToChat) != 0; }
bool GetAllowObservers() const { return (mNewGroupFlags & RoutingGroupFlag_AllowObservers) != 0; }
bool GetAllowObserversToChat() const { return (mNewGroupFlags & RoutingGroupFlag_AllowObserversToChat) != 0; }
bool GetDetailedObservers() const { return (mNewGroupFlags & RoutingGroupFlag_DetailedObservers) != 0; }
bool GetIsInviteOnly() const { return (mNewGroupFlags & RoutingGroupFlag_InviteOnly) != 0; }
bool GetAskCaptainToJoin() const { return (mNewGroupFlags & RoutingGroupFlag_AskCaptainToJoin) != 0; }
bool GetAskCaptainToObserve() const { return (mNewGroupFlags & RoutingGroupFlag_AskCaptainToObserve) != 0; }
bool GetNoCaptain() const { return (mNewGroupFlags & RoutingGroupFlag_NoCaptain) != 0; }
bool GetIsChatRoom() const { return (mNewGroupFlags & RoutingGroupFlag_IsChatRoom) != 0; }
virtual RoutingOpType GetType() const { return RoutingOp_GroupFlagsChanged; }
};
typedef SmartPtr<RoutingGroupFlagsChangedOp> RoutingGroupFlagsChangedOpPtr;
}; // namespace WONAPI
#endif
|
Talking Set Top Box makes Digital TV Accessible
Senator Stephan Conroy announced the commercial release of a talking set top box that will aid and encourage the visually impaired to use digital television.
The new talking set top box was announced today by the Minister of Broadband, Communications and the Digital Economy, Senator Stephan Conroy.
"For the first time in Australia, vision impaired people will be able to enjoy significantly enhanced benefits of digital television," said Conroy.
The talking set top box will read out onscreen menus, electronic program guides, and settings of their television.
The box uses text-to-speech technology to describe programs, menu items, and menu layouts. It benefits from a 'key-learn' feature for the remote control and can have its speech style changed.
"This kind of technology has been developed in other countries, however, no talking set-top box was available in the Australian market until now," Conroy said.
"Today's announcement coincides with Queensland Disability Action Week and marks a significant achievement for the Government and industry to make digital TV accessible to all Australians."
In developing the new set top box the government worked closely with the industry and tested the technology in the Household Assistance Scheme rollout in regional Victoria.
"The talking set-top box trial was designed to test this innovative technology with vision impaired Victorians. I am delighted to see this initiative result in the commercial release of a talking set-top box to the broader Australian community."
The Household Assistance Scheme provides free digital TV help for maximum aged pensioners and has assisted 50,000 eligible households throughout South Australia, Victoria and Queensland.
With the trials success, the government is now pursuing operational and funding requirements to have the talking set top box incorporated under the scheme.
"Australia is striding forward in the global migration to digital TV with 82 per cent of households across the nation already converted to digital TV," Senator Conroy said.
"The Australian Government is committed to ensuring that no-one is left behind in the switch to digital-only television." |
Q:
Client-server synchronization over REST
This question is about what I think is a very common problem in Android / iOS development but I haven't found any "standard" solution yet.
Let's say we have a fairly normal REST API. The server database contains (among others) the tables countries and towns with a 1:N relationship.
The client (mobile app) wants to maintain a local snapshot of these two tables. So that when it's offline, it can do queries that would be normally done over REST, e.g.: "get a list of Austrian towns with population >= 100"?
How to approach this?
First problem: consistency. The client should have a snapshot of the two tables. If the client downloads updates of the towns table and goes offline, some town may reference a country that's not in the local copy of the countries table.
Second problem: the client should only download the new / deleted / changed rows. Ditch the REST and use some custom RPC call like get_updates_since(...)?
Third problem: how should local changes to the client's copy of the database (possibly made offline) be synchronized with the server? Custom RPC calls?
A:
I don't think there's a silver bullet but the pattern you're looking for is caching. In past projects I have copied items from the server to local storage (SQLite or flat file), and maintained meta-data about the entries to update/upload/purge based on simple rules. It's not a simple problem and ends up being a lot of code.
Consistency: in your example, either ensure you download the countries table first, or make the two operations atomic - e.g., make copies of the "new" tables and only replace your cached versions if both copies complete successfully (doubles up on storage).
Only download new/deleted/changed: Yep, this requires client/server integration - timestamp all the records (with GMT), ask for metadata from the server, and walk through your local metadata deciding what to do. (Hint UUIDs on the rows are helpful).
Synchronize local changes: Yes, more client/server integration. See above paragraph.
Handling all the exceptions and edge cases is challenging. Take a look at the problems with iCloud sync'ing CoreData. Perhaps not a fair comparison, as Apple is trying to solve this for a totally distributed database, but interesting reading nonetheless.
A:
Currently I am working on the same task - building the Android app which would sync info with a central SQL database using Azure Mobile Services. The sync strategy is to support bidirectional sync from multiple clients to ensure data consistency whereas only incremental changes will be exchanged.
Let me provide my solution to your problems.
I recently wrote a blog post about sync algorithm to support this scenarios.
The sync logic will be managed on the client side because of REST API communication.
Each table participating in the sync process will have the corresponding REST Api methods for CRUD operations.
For your first problem (consistency) – the solution is to download data on the client in correct order. E.g. first parents, then children to avoid problems with referential integrity. In case of network problem the client would have to sync again to get the rest of data.
Second problem (download only incremental changes) – the solution is timestamp (as Kevin mentioned in his answer below). But I would suggest using globally incremented value maintained on the server side to avoid issues with timestamp differences between clients and server. The rowversion of SQL Server is quite good candidate for this.
Third problem (data integration from the client) – using Dirty flag in the client tables would help to differentiate the records required for upload.
You might also need to introduce the Delete flag on both sides to handle deletes between multiple clients.
|
<!-- vim: set ai sw=1 ts=1 sta et: -->
<models>
<model name="RAMB36E1_PRIM">
<input_ports>
<!-- Port A - 32bit wide -->
<port is_clock="1" name="CLKARDCLKU" />
<port is_clock="1" name="CLKARDCLKL" />
<port clock="CLKARDCLKL" name="ENARDENU" />
<port clock="CLKARDCLKL" name="ENARDENL" />
<port clock="CLKARDCLKL" name="REGCEAREGCEU" />
<port clock="CLKARDCLKL" name="REGCEAREGCEL" />
<port clock="CLKARDCLKL" name="REGCLKARDRCLKU" />
<port clock="CLKARDCLKL" name="REGCLKARDRCLKL" />
<port clock="CLKARDCLKL" name="RSTRAMARSTRAMU" />
<port clock="CLKARDCLKL" name="RSTRAMARSTRAMLRST" />
<port clock="CLKARDCLKL" name="RSTREGARSTREGU" />
<port clock="CLKARDCLKL" name="RSTREGARSTREGL" />
<port clock="CLKARDCLKL" name="ADDRARDADDRU" />
<port clock="CLKARDCLKL" name="ADDRARDADDRL" />
<port clock="CLKARDCLKL" name="DIADI" />
<port clock="CLKARDCLKL" name="DIPADIP" />
<port clock="CLKARDCLKL" name="WEAU" />
<port clock="CLKARDCLKL" name="WEAL" />
<!-- Port B - 32bit wide -->
<port is_clock="1" name="CLKBWRCLKU" />
<port is_clock="1" name="CLKBWRCLKL" />
<port clock="CLKBWRCLKL" name="ENBWRENU" />
<port clock="CLKBWRCLKL" name="ENBWRENL" />
<port clock="CLKBWRCLKL" name="REGCEBU" />
<port clock="CLKBWRCLKL" name="REGCEBL" />
<port clock="CLKBWRCLKL" name="REGCLKBU" />
<port clock="CLKBWRCLKL" name="REGCLKBL" />
<port clock="CLKBWRCLKL" name="RSTRAMBU" />
<port clock="CLKBWRCLKL" name="RSTRAMBL" />
<port clock="CLKBWRCLKL" name="RSTREGBU" />
<port clock="CLKBWRCLKL" name="RSTREGBL" />
<port clock="CLKBWRCLKL" name="ADDRBWRADDRU" />
<port clock="CLKBWRCLKL" name="ADDRBWRADDRL" />
<port clock="CLKBWRCLKL" name="DIBDI" />
<port clock="CLKBWRCLKL" name="DIPBDIP" />
<port clock="CLKBWRCLKL" name="WEBWEU" />
<port clock="CLKBWRCLKL" name="WEBWEL" />
<!-- FIXME -->
<port name="CASCADEINA" />
<port name="CASCADEINB" />
</input_ports>
<output_ports>
<!-- Port A - 32bit wide -->
<port clock="CLKARDCLKL" name="DOADO" />
<port clock="CLKARDCLKL" name="DOPADOP" />
<!-- Port B - 32bit wide -->
<port clock="CLKBWRCLKL" name="DOBDO" />
<port clock="CLKBWRCLKL" name="DOPBDOP" />
<!-- FIXME -->
<port name="CASCADEOUTA" />
<port name="CASCADEOUTB" />
</output_ports>
</model>
</models>
|
Q:
RGB value to HSL converter
Google maps api v3 allows "styles" to be applied to the map, including setting the color of various features. However, the color format it uses is HSL (or what seems like it):
hue (an RGB hex string)
lightness (a floating point value between -100 and 100)
saturation (a floating point value between -100 and 100)
(from the docs)
I managed to find RGB to HSL converters online, but I am unsure how to specify the converted values in a way that google maps will accept. For instance, a typical HSL value given by a converter would be: 209° 72% 49%
How does that HSL value map to the parameters I specified from the google maps api? i.e. how does a hue degree value map to an RGB hex string and how does a percentage map to a floating point value between -100 and 100?
I am still uncertain how to do the conversion. I need to, given an RGB value, quickly convert it to what google maps expects so that the color will be identical...
A:
Since the hue argument expects RGB, you can use the original color as the hue.
rgb2hsl.py:
#!/usr/bin/env python
def rgb2hsl(r, g, b):
#Hue: the RGB string
H = (r<<16) + (g<<8) + b
H = "0x%06X" % H
#convert to [0 - 1] range
r = float(r) / 0xFF
g = float(g) / 0xFF
b = float(b) / 0xFF
#http://en.wikipedia.org/wiki/HSL_and_HSV#Lightness
M = max(r,g,b)
m = min(r,g,b)
C = M - m
#Lightness
L = (M + m) / 2
#Saturation (HSL)
if L == 0:
S = 0
elif L <= .5:
S = C/(2*L)
else:
S = C/(2 - 2*L)
#gmaps wants values from -100 to 100
S = int(round(S * 200 - 100))
L = int(round(L * 200 - 100))
return (H, S, L)
def main(r, g, b):
r = int(r, base=16)
g = int(g, base=16)
b = int(b, base=16)
print rgb2hsl(r,g,b)
if __name__ == '__main__':
from sys import argv
main(*argv[1:])
Example:
$ ./rgb2hsl.py F0 FF FF
('0xF0FFFF', 100, 94)
Result:
Below is a screenshot showing the body set to a rgb background color (#2800E2 in this case), and a google map with styled road-geometry, using the values calculated as above ('0x2800E2', 100, -11).
It's pretty clear that google uses your styling to create around six different colors centered on the given color, with the outlines being closest to the input. I believe this is as close as it gets.
From experimentation with: http://gmaps-samples-v3.googlecode.com/svn/trunk/styledmaps/wizard/index.html
For water, gmaps subtracts a gamma of .5. To get the exact color you want, use the calculations above, and add that .5 gamma back.
like:
{
featureType: "water",
elementType: "geometry",
stylers: [
{ hue: "#2800e2" },
{ saturation: 100 },
{ lightness: -11 },
{ gamma: 0.5 },
]
}
A:
We coded a tool which exactly does want you want. It takes hexadecimal RGB values and generates the needed HSL code. It comes with a preview and Google Map JavaScript API V3 code output. Enjoy ;D
http://googlemapscolorizr.stadtwerk.org/
|
Abstract Addiction neuroscience models posit that recurrent drug use increases reactivity to drug-related cues and blunts responsiveness to natural rewards, propelling a cycle of hedonic dysregulation that drives addictive behavior. Here, we assessed whether a cognitive intervention for addiction, Mindfulness-Oriented Recovery Enhancement (MORE), could restructure reward responsiveness from valuation of drug-related reward back to valuation of natural reward. Before and after 8 weeks of MORE or a support group control, prescription opioid users (N = 135) viewed opioid and natural reward cues while an electroencephalogram biomarker of target engagement was assessed. MORE was associated with decreased opioid cue-reactivity and enhanced capacity to regulate responses to opioid and natural reward cues. Increased positive affective responses to natural reward cues were associated with decreased craving and mediated MORE’s therapeutic effects on opioid misuse. This series of randomized experiments provide the first neurophysiological evidence that an integrative behavioral treatment can remediate hedonic dysregulation among chronic opioid users.
INTRODUCTION Currently, the United States is in the midst of an opioid crisis. In 2015, 91.8 million U.S. adults used prescription opioids, and among these individuals, 16.7% reported an opioid use disorder (OUD) (1). The opioid crisis confronting the United States is thought to have emerged in large part from misuse of opioid analgesic medications prescribed for pain management. Chronic opioid use may render vulnerable individuals at risk for developing opioid misuse and OUD due to neuropsychopharmacological effects of opioids on reward processing and hedonic regulation in the brain (2). Allostatic models have been advanced to explicate the downward spiral leading to opioid misuse and OUD (3, 4). These models posit that prolonged opioid use may shift hedonic set points in corticostriatal circuitry mediating reward and disrupt capacity to proactively regulate responses to emotional stimuli. Consequently, addiction involves a process of hedonic dysregulation, in which the motivation to obtain natural rewards is reorganized around seeking drug-associated reward and the desire to alleviate aversive states (e.g., stress and pain) (5). During the process of hedonic dysregulation, chronic use of drugs of abuse, including opioids, produces neurobiological alterations that increase the incentive salience of drug-related cues (6), resulting in heightened drug cue-reactivity and craving while, at the same time, decreasing sensitivity to natural reward derived from homeostatic goal attainment (7). The downward shift in salience of natural reward relative to drug reward may represent a crucial tipping point leading to the loss of control over drug use that is characteristic of addiction. Hedonic dysregulation can be indexed by neurophysiological responses measured at the scalp via event-related potential (ERP) analysis of the electroencephalogram (EEG) and, specifically, by the late positive potential (LPP) of the EEG. Bottom-up processing of motivationally salient stimuli elicits a larger LPP than neutral stimuli that tends to reach maximum amplitude along the midline at centroparietal sites (Cz and Pz) between 400 and 800 ms after image onset (8). Simultaneous EEG and functional magnetic resonance imaging (fMRI) recordings demonstrate that the magnitude of the LPP during processing of motivationally salient stimuli is associated with blood oxygen level–dependent (BOLD) activity in emotion-processing structures like the amygdala, insula, and orbitofrontal cortex (9). Unlike earlier ERP components such as N200 and P300, thought to reflect cognitive control, novelty detection, and initial attentional orienting to an unexpected stimulus (10, 11), the LPP is theorized to reflect sustained, motivated attention to the emotional features of a stimulus (8). In that regard, LPP amplitude remains significantly larger for emotional stimuli than neutral stimuli to at least 1500 ms (12) and is robustly correlated with subjective ratings of arousal in response to emotional images (13). Furthermore, the LPP is subject to top-down regulation (14): that is, the proactive use of cognitive processes to increase (up-regulation) or decrease responses (down-regulation) to a motivationally salient stimulus. Attempts to consciously regulate responding to emotional stimuli result in amplitude changes in the LPP that reflect regulatory efficacy—with attentional deployment regulatory strategies operating as early as 700 to 900 ms and evaluative emotion regulation strategies operating as late as 1500 ms (14). Individuals with substance use disorders exhibit a greater LPP to drug-related cues than to neutral cues and cues representing natural rewards (15). LPP indices of drug cue-reactivity predict increased craving (16) and reverse after a period of extended abstinence (17). Thus, the LPP represents an EEG biomarker of clinical target engagement in addiction treatment. Moreover, ERPs have been used to assess hedonic dysregulation among individuals with OUD who exhibit blunted ERPs to stimuli representing natural rewards relative to ERPs to drug cues (18). This decreased responsiveness to natural reward relative to drug reward significantly predicts future opioid consumption (19). Hence, efficacious addiction therapies that aim to down-regulate drug cue-reactivity and up-regulate responsiveness to natural rewards should modulate the LPP as evidence of target engagement. Thus far, few studies have examined the effect of psychosocial therapies on neural indices of drug cue-reactivity; a recent review identified only four small randomized controlled trials (RCTs) and none in chronic prescription opioid users (20). Among psychosocial treatments, mindfulness-based interventions might be especially promising means of reducing drug cue-reactivity, given their established efficacy in reducing substance use and misuse (21). Neurocognitive models of mindfulness-centered regulation of addictive responses suggest that mindfulness-based interventions might decrease bottom-up cue-reactivity responses and improve top-down regulation of these responses (22). To date, these hypotheses have been tested in only two studies: a laboratory-based, within-subjects study, which found that a mindfulness induction reduced smoking cue-reactivity in the subgenual anterior cingulate cortex (23), and a quasi-experimental study, which found that a multiweek mindfulness-based intervention significantly reduced smoking cue-reactivity in the striatum (24). To our knowledge, the effects of mindfulness-based interventions on neurophysiological markers of drug cue-reactivity have not been assessed via randomized controlled pretest-posttest designs. However, a mindfulness-based intervention for prescription opioid misuse that demonstrated efficacy in two stage 2 RCTs (25, 26), Mindfulness-Oriented Recovery Enhancement (MORE), was shown to significantly decrease opioid cue-reactivity, as manifested by decreased attentional bias (27) and cue-elicited craving responses (28). Similarly, MORE was shown to enhance autonomic (28) and electrocortical (29) responses to natural rewards among prescription opioid users, suggesting that this therapy may effectively target hedonic dysregulation in addiction. MORE is a cognitive training program that integrates skills designed to promote sustained attention to natural rewards with mindfulness and reappraisal techniques. Given its focus on orienting attention away from drug-related cues and toward healthful and socially affiliative objects and events, it is plausible that MORE may shift the relative salience of drug and natural rewards. Our restructuring reward hypothesis states that restructuring reward processing from valuation of drug-related reward back to valuation of natural rewards will reduce craving and addictive behavior (30). Thus, we expect that decreases in drug cue-reactivity and appetitive responses will be paralleled by improved capacity to down-regulate drug cue responses and up-regulate responsiveness to natural rewards. Here, we methodically investigated the effects of MORE on bottom-up cue-reactivity and top-down regulation of responding to reward-related stimuli in the context of chronic prescription opioid use in an attempt to test the postulates of the restructuring reward hypothesis. To do so, we used experimental tasks in which participants viewed and regulated responses to stimuli representing drug and nondrug natural rewards. We conducted a series of four experiments across three samples of chronic prescription opioid users that in toto were designed to test the restructuring reward hypothesis vis-à-vis chronic use of prescription opioids. In experiment 1, chronic opioid users completed a blocked cue-reactivity task before and after being treated with MORE or an active support group (SG) control condition to determine whether MORE could decrease bottom-up reactivity to opioid cues. In experiment 2, chronic opioid users completed an event-related cue-reactivity task before and after MORE or an SG control to determine whether MORE could enhance down-regulation of opioid cue-reactivity versus passive viewing of opioid cues. In experiment 3, chronic opioid users completed an event-related cue-reactivity task before and after MORE or an SG control to determine whether MORE could enhance up-regulation of neurophysiological responses to naturally rewarding stimuli. In experiment 4, we examined data from a blocked cue-reactivity task implemented as a mechanistic aim from a clinical trial (NCT03298269) to determine whether MORE could enhance subjective emotional responses to naturally rewarding stimuli, and whether doing so was associated with decreases in craving and clinical improvements in opioid misuse behavior. In 135 chronic opioid users participating across four experiments, we found neurophysiological and behavioral patterns indicating that MORE may reduce opioid cue-reactivity by increasing top-down regulatory control and boosting responsiveness to natural rewards, effects that were associated with reduced addictive behaviors and in line with the restructuring reward hypothesis. We therefore suggest that targeting reward system function with integrative behavioral treatments and other cognitive training interventions may provide the learning signal needed to restore adaptive hedonic regulation and, ultimately, to reverse addiction.
RESULTS We collected data in four experiments in which chronic opioid users (average duration of opioid use, 10.13 ± 7.17 years; see Table 1 for other demographic and clinical characteristics) performed different versions of a cue-reactivity task (see Materials and Methods). On each trial, participants (N = 135) saw an emotionally salient (i.e., opioid- or natural reward–related) image or neutral image and then were asked to merely view the image or (in the case of an emotionally salient image) to regulate their response to the image. During these tasks, EEG was recorded (see Materials and Methods). The experiments differed with regard to their design parameters (blocked versus event-related design) and their focus on a particular image type (opioid versus natural reward) and whether the regulation condition was central to the subhypothesis under question. On regulation trials in response to opioid-related images, participants were instructed to down-regulate their response to the image by adopting a nonreactive attentional stance toward the image while maintaining meta-awareness of their thoughts, emotions, and body sensations. These instructions parallel those used in other laboratory-based research of the effects of state mindfulness on drug cue-reactivity (23). On regulation trials in response to natural reward–related images, participants were instructed to up-regulate their response to the image by savoring the pleasant, beautiful, or meaningful aspects of the image and immersing themselves in the positive emotions and pleasurable body sensations elicited by the image. These instructions parallel those used in other studies of MORE (24). Table 1 Demographic and clinical characteristics of the chronic opioid using samples (N = 135). View this table: Verification of successful opioid cue-reactivity at pretreatment via neurophysiological responses As a prerequisite, we assessed the quality and validity of our experimental cue-reactivity design, irrespective of the effects of treatment. At pretreatment, opioid cues elicited significantly greater centroparietal LPP than neutral cues (t 39 = 4.28, P < 0.001), indicating the presence of opioid cue-reactivity in this chronic opioid using sample. However, at pretreatment, LPPs did not significantly differ by group assignment (F 1,38 = 0.02, P = 0.89, η partial 2 < 0.01), indicating that randomization was successful in generating groups that were equivalent at baseline. Treatment effects on neurophysiological responses to opioid cues Experiment 1 assessed the effects of treatment on LPP indices of opioid cue-reactivity relative to reactivity to neutral cues (Fig. 1). In repeated-measures analysis of variance (RM-ANOVA) of signal-averaged LPP data, the Group × Time × Stimulus Type interaction indicated significant effects of MORE versus the active SG control condition on LPP opioid cue-reactivity. Relative to the SG control, MORE was associated with significantly greater decreases in LPP response to opioid cues (relative to neutral cues) from pretreatment to posttreatment (F 1,37 = 4.89, P = 0.033, η partial 2 = 0.12). Within-group comparisons indicated that for individuals in the SG, posttreatment LPP activations remained significantly higher in response to opioid cues compared to the neutral cues, suggesting that participants in the SG continued to exhibit opioid cue-reactivity (t 20 = 5.93, P < 0.001). In contrast, for individuals in the MORE group, there were no significant differences in posttreatment LPP activations between opioid and neutral cue conditions (t 18 = 0.30, P = 0.77). Fig. 1 Experiment 1: Treatment effects on centroparietal LPP during opioid cue-reactivity. (A) Experiment 1: Treatment by time effects on centroparietal LPP during opioid cue-reactivity. (B) Experiment 1: Change in centroparietal LPP (in μV) index of opioid cue-reactivity (opioid cue − neutral cue) from pretreatment to posttreatment (n = 40). Treatment effects on the down-regulation of neurophysiological responses to opioid cues Experiment 2 assessed the effects of treatment on the capacity to down-regulate the LPP response to opioid cues (Fig. 2). In RM-ANOVA of signal-averaged LPP data, the Group × Time × Condition interaction indicated significant effects of MORE versus the active SG control condition on LPP responses (regulate < view) to opioid cues. Relative to those in the SG, participants who were treated with MORE exhibited significantly greater decreases in the LPP response to opioid cues during regulation (regulate < view) from pretreatment to posttreatment (F 1,21 = 7.22, P = 0.014, η partial 2 = 0.26). Fig. 2 Experiment 2: Treatment effects on centroparietal LPP during down-regulation of opioid cue-reactivity. (A) Experiment 2: Treatment by time effects on centroparietal LPP during down-regulation of opioid cue-reactivity. (B) Experiment 2: Change in centroparietal LPP (in μV) index of regulation of opioid cue-reactivity (regulate-view) from pretreatment to posttreatment (n = 24). Treatment effects on the up-regulation of neurophysiological responses to natural reward cues Experiment 3 assessed the effects of treatment on the capacity to up-regulate the LPP response to natural reward cues (Fig. 3). In RM-ANOVA of signal-averaged LPP data, the Group × Time × Condition interaction indicated significant effects of MORE versus the active SG control condition on LPP responses (regulate > view) to natural reward cues. Relative to those in the SG, participants who were treated with MORE exhibited significantly greater increases in the LPP response to natural reward cues during regulation (regulate > view) from pretreatment to posttreatment (F 1,26 = 4.79, P = 0.038, η partial 2 = 0.16). Fig. 3 Experiment 3: Treatment effects on centroparietal LPP during up-regulation of natural reward. (A) Experiment 3. Treatment by time effects on centroparietal LPP during up-regulation of natural reward. (B) Experiment 3: Change in LPP (in μV) index of regulation of natural reward cue-reactivity (regulate − view) from pretreatment to posttreatment (n = 29). Regulatory effects on relative responsiveness to drug and natural rewards To examine the effects of regulation on relative responsiveness to drug and natural rewards, we computed a relative responsiveness measure by subtracting LPP regulatory response to opioid cues from LPP regulatory response to natural reward cues (regulate − view difference scores). Comparable measures of differential responsiveness to drug and natural reward images have been used in previous LPP research in populations with substance use disorders (17). A similar contrast, in which drug approach behavior is assessed in the context of a contemporaneously available natural reward, is used in drug choice paradigms in both humans and animals (31). This contrast was recently shown to predict opioid misuse following behavioral treatment (32) and parallels a key diagnostic criterion for substance use disorder: compulsive use of the drug of choice to the exclusion of other rewarding activities. When compared to those in the SG, participants treated with MORE exhibited significantly greater increases in the LPP measure of relative responsiveness to natural reward relative to drug reward from pretreatment to posttreatment (F 1,21 = 10.00, P = 0.005, η partial 2 = 0.32). Treatment effects on the regulation of affective and craving responses to natural reward cues Experiment 4 evaluated affect ratings in response to natural reward cues collected from a sample opioid-treated chronic pain patients participating in a stage 2 RCT of MORE. In RM-ANOVA, the Group × Time interaction indicated significant effects of MORE versus an SG control condition in affect ratings. Relative to those in the SG, participants who were treated with MORE exhibited significantly greater positive affective response to natural reward cues from pretreatment to posttreatment (F 1,62 = 6.00, P = 0.017, η partial 2 = 0.09) (Fig. 4A). However, this increase in positive affective response to natural reward cues did not significantly differ on regulate versus view trials (F 1,62 = 1.52, P = 0.22, η partial 2 = 0.02). Fig. 4 Experiment 4: Treatment effects on positive affect and craving ratings across view and regulate conditions of the natural reward cue-reactivity task. (A) Experiment 4: Change in positive affect ratings (log transformed) across view and regulate conditions of the natural reward cue-reactivity task from pretreatment to posttreatment (n = 64). (B) Experiment 4: Change in craving ratings (log-transformed) during up-regulation of natural reward cue-reactivity (regulate − view) from pretreatment to posttreatment (n = 64). (C) Experiment 4: Associations between treatment-related changes in positive affect reactivity and decreases in craving during up-regulation of responding to natural reward (n = 64). Note that several cases had identical change scores and are therefore represented by a single data point in the scatterplot. As a secondary outcome of our fourth experiment, we examined the effects of treatment on opioid craving ratings in response to natural reward cues (Fig. 4B). In RM-ANOVA, the Group × Time × Condition interaction indicated that, relative to those in the SG, participants who were treated with MORE exhibited significantly greater decreases in craving from pretreatment to posttreatment during up-regulation of response to natural reward cues from pretreatment to posttreatment (F 1,62 = 11.09, P = 0.001, η partial 2 = 0.15). However, the craving-reducing effect of MORE was only evident during regulation but not during view trials (F 1,62 = 1.09, P = 0.30, η partial 2 = 0.02). Decreases in craving response were associated with increases in positive affective response to natural reward cues from pretreatment to posttreatment (r = −0.41, P = 0.001) (Fig. 4C). Increases in natural reward responsiveness mediate the effect of MORE on reduced opioid misuse Also in experiment 4, path analysis revealed that the effect of MORE on decreases in opioid misuse scores was mediated by increases in natural reward responsiveness from pretreatment to posttreatment [B = 1.28; SE = 0.62; P = 0.04; 95% confidence interval (CI), 0.29 to 2.79] (Fig. 5). The overall model explained 30% of the variance in changes in opioid misuse scores measured by the Current Opioid Misuse Measure [COMM; (33)]. Fig. 5 Path analysis demonstrating that the effect of MORE on reducing opioid misuse by 3-month follow-up is mediated by increased positive affective reactivity to natural reward cues. These findings, when combined with the aforementioned craving-reducing effects of up-regulation of responding to natural reward cues, provide direct support for the restructuring reward hypothesis. Mindfulness practice and restructuring reward To determine whether more intensive practice of mindfulness-related skills was associated with greater restructuring of neurophysiological and subjective reward processes, we examined correlations between the duration of mindfulness practice and changes in reward-related processes among participants treated with MORE. Total number of minutes of mindfulness practice was associated with decreases in LPP opioid cue-reactivity (r = −0.73, experiment 1), minutes of mindful breathing practice were associated with increases in the capacity to regulate LPP responses to natural reward relative to drug reward (r = 0.63, experiments 2 and 3), and minutes of savoring practice were associated with reductions in craving during up-regulation of responding to reward cues (r = −0.49, experiment 4).
DISCUSSION For decades, hedonic dysregulation in brain reward circuitry has been considered a core mechanism of addictive behavior (5); therefore, successful addiction treatments should restructure reward processes by decreasing reactivity to drug cues while increasing reactivity to naturally rewarding objects and events in the social environment. However, to date, no treatment approach has demonstrated both of these effects via neurophysiology in a single, randomized controlled study. In the present investigation, we used several variations of a cue-reactivity task to investigate the effects of a mindfulness-based treatment, MORE, on hedonic regulation of responses to drug and natural reward–related cues among chronic prescription opioid users. Here, across four experiments and 135 participants, we reveal neurophysiological and psychological evidence in support of the restructuring reward hypothesis, suggesting that modulating hedonic responses to drug-related and natural rewards may have a therapeutic impact on addiction. Before treatment, chronic prescription opioid users in the present study exhibited opioid cue-reactivity, evidenced by heightened LPP responses to opioid-related images relative to neutral images. Compared to opioid users in an active control condition, opioid users treated with MORE evidenced significantly reduced opioid cue-reactivity, as revealed by the LPP—an index of attention to emotional information (8). Following 8 weeks of treatment, individuals participating in the control condition continued to show significant LPP opioid cue-reactivity, whereas participants who received the MORE intervention did not exhibit significantly different LPP responses to opioid and neutral images. This attenuated opioid cue-reactivity following treatment with MORE suggests that MORE might decouple associations between conditioned drug cues and their reward value via bottom-up mechanisms. Although MORE significantly modulated the LPP, a known EEG biomarker of clinical target engagement in addiction (15–17), in the present study, we were unable to ascertain whether the observed neurophysiological changes were associated with changes in opioid misuse behaviors. Furthermore, when participants were instructed to consciously down-regulate opioid cue-reactivity, MORE augmented this capacity, as evidenced by significantly greater attenuations in the LPP following 8 weeks of treatment with MORE than the active control condition. Regulatory instructions in this study corresponded to typical mindfulness training instructions to adopt a state of meta-awareness in which one monitors and accepts thoughts, emotions, and body sensations as they arise without attempting to suppress or sustain them. To control for demand characteristics, regulatory instructions were kept constant across both treatment conditions at both assessment time points, allowing us to isolate the effects of mindfulness training through the MORE intervention from any potential instruction effects. The observed LPP modulations suggest that MORE facilitates top-down, mindfulness-centered regulation of cue-reactivity, a finding that supports prominent neurocognitive models of mindfulness as a treatment for addiction (22). To our knowledge, this study provides the first evidence from an experiment using a randomized, controlled pretest-posttest design that a mindfulness-based intervention can significantly reduce neural indices of drug cue-reactivity. In parallel with the observed effects on reactivity to drug-related reward stimuli, we obtained neurophysiological evidence that MORE strengthens the capacity to consciously up-regulate responsiveness to natural reward stimuli. At pretreatment, when participants in both conditions were provided the regulatory instruction to savor the pleasant sensory features and positive affective meaning associated with images of natural rewards (e.g., social affiliation, natural beauty, and athletic victories), they were unable to do so, evidenced by little change in LPP response from simply viewing the images. Of note, in previous research, opioid misusing chronic pain patients evidenced an inability to consciously up-regulate responsiveness to natural reward stimuli, as indicated by blunted autonomic responses during savoring (33). However, among healthy controls, focusing attention on the reward value of a stimulus can enhance the LPP in response to that stimulus (34), indicating that such up-regulation is possible. Following 8 weeks of MORE, which involves daily practice of mindful savoring, participants were able to significantly up-regulate the LPP to natural reward cues when savoring relative to passively viewing the images. Because previous research found that MORE was associated with significantly increased LPP reactivity during viewing of natural reward images relative to neutral images (29), we did not opt to replicate this experiment here. Instead, the present randomized controlled experiment extends these findings by suggesting that, in addition to increasing bottom-up reactivity to natural rewards, MORE may strengthen top-down regulatory capacity to consciously amplify natural reward responses—congruent with fMRI findings from a previous quasi-experimental evaluation of MORE (24). MORE was associated with increased capacity to regulate responsiveness to natural reward images relative to drug-related images. This neurophysiological finding parallels cardiac autonomic evidence from a randomized controlled study of chronic opioid users indicating that MORE shifts relative responsiveness from drug cues to natural reward cues, a shift that predicts decreased opioid misuse following treatment (35). Similarly, among individuals with cocaine use disorder (who exhibit heightened LPP to drug images relative to natural reward images at baseline), longer periods of abstinence are associated with a reversal of this relative responsiveness measure such that motivated attention is allocated more toward natural reward cues than drug cues—a neurophysiological change correlated with decreased craving (17). Furthermore, greater responsiveness to drug cues relative to natural reward cues predicts relapse among individuals with OUD (19). In the context of these previous findings, evidence from the present study that MORE is associated with increased LPP in response to natural reward cues relative to drug cues may have important implications for addiction treatment outcomes among chronic opioid users. In that regard, for our final experiment in this study, we analyzed data from a mechanistic probe of natural reward responsiveness included in recently completed stage 2 RCT of MORE. In this trial, MORE was shown to significantly reduce opioid misuse risk by 3 months following the end of treatment (26). Here, using a variant of the cue-reactivity task described above, we found evidence that MORE significantly increased positive affective reactivity to natural reward cues from pretreatment to posttreatment, irrespective of any conscious regulatory attempts. In contrast, when participants treated with MORE engaged in conscious up-regulation of responding to natural reward cues by savoring the pleasant aspects of the cue, these regulatory efforts significantly decreased opioid craving from baseline levels—decreases that were associated with increased positive affect reactivity over the course of treatment. In complementary fashion, increases in positive affective reactivity to natural reward cues mediated the effect of MORE on decreasing opioid misuse by 3-month follow-up. Together with the neurophysiological findings described above, study results provide support for the restructuring reward hypothesis, suggesting that shifting valuation from drug-related reward back to valuation of natural reward decreases craving and addictive behavior. MORE is a sequenced treatment designed to modify associative learning mechanisms hijacked during the allostatic process of addiction by strengthening top-down cognitive control to restructure bottom-up reward learning from valuation of drug reward back to valuation of natural reward. In MORE, patients initially practice mindfulness to build capacity for attention regulation and meta-awareness. Later, mindfulness skills are used to synergize more elaborate therapeutic techniques designed to restructure valuation processes underpinning addiction. In that regard, MORE provides instruction in using mindfulness to disengage attention from addiction-related interoceptive and exteroceptive cues and then shift and sustain attention on the pleasant sensory features of healthful experiences. Mindfulness is also used to metacognitively reflect on positive emotions or higher-order meaning arising in response to rewarding stimuli. This “mindful savoring” technique is intended to broaden and deepen the array of pleasurable sensations derived from the savored experience. Restructuring of reward processing in MORE may arise from restoration of a frontostriatal feedback loop involved in executive control of motivated behavior and reward learning (22). In this regard, dopaminergic and opioidergic systems implicated in salience attribution and hedonic responses are known to be dysregulated in the context of addiction and chronic pain (4). It is possible that MORE would facilitate the functional recovery of these mechanisms. Additional neuroimaging research would now be indicated to localize the neural generators of the observed shifts in reward responsiveness. Despite its strengths, this study had several limitations. First, this investigation was a mechanistic study—not a clinical trial powered to detect changes in treatment outcomes. However, two stage 2 RCTs demonstrated the efficacy of MORE for reducing opioid misuse among opioid-treated chronic pain patients (25, 26), and a stage 3 RCT of MORE is currently underway. Relatedly, it is unknown whether the observed modulations in LPP responses reflect direct changes in clinical outcomes, in the therapeutic mechanisms that lead to them, or indirect effects that might not be associated with behavioral improvements. As a plausible alternative interpretation of the current study findings, it is possible that the observed modulations of LPP function were due to reductions in opioid intake over the course of the study. Reduction in opioid intake, in turn, might improve the function of the mesolimbic reward system. To account for this possibility, we controlled for posttreatment opioid dose in our ERP analyses, suggesting that the observed effects on reward processing are at least partially independent from the neuropharmacological effects of opioid consumption. In addition, the study was limited by the moderate amount of noise in the ERP data from experiments 2 and 3 due to the modest sample size and the fact that we used relatively few trials per condition. We chose to present a limited number of trials during these two experiments to reduce participant burden because the participants in these experiments—military veterans with opioid-treated chronic pain—were highly vulnerable and therefore unable/unwilling to sit still for a long experimental protocol. Psychometric analyses of the LPP indicate that 12 trials per condition are needed to obtain stable difference waves (36); thus, our experiments were designed to generate LPPs with adequate internal consistency, and despite the noise, we identified a significant signal associated with participation in the MORE intervention. In the future, fully powered replication studies with larger sample sizes and a greater number of trials per condition could generate more stable, reliable estimates of the effects of MORE on LPP responses. The present EEG analysis was also limited in its spatial resolution. Future studies could use high-density EEG arrays (128 or 256 electrodes) to allow better localization of the observed neurophysiological effects of MORE. Last, MORE integrates mindfulness training with reappraisal and savoring techniques, and any of these techniques, separately or in synergy, might restructure reward responsiveness. Future trials could use dismantling designs to parse neural effects of intervention components. In summary, the present series of experiments suggests that MORE may remediate hedonic dysregulation among chronic opioid users by increasing responsiveness to natural reward while simultaneously decreasing reactivity to drug-related reward. Restructuring reward processing through cognitive training interventions like MORE may modulate core addiction mechanisms by reversing the shift in salience of natural reward relative to drug reward, providing a novel therapeutic target and representing a crucial tipping point to halt the ongoing opioid crisis.
MATERIALS AND METHODS Participants Participants (N = 135) were recruited from primary care and pain clinics in Salt Lake City, UT through electronic health record review, opt-out letters, flyers, and radio advertisements. Advertisements recruited individuals who suffered from, and were prescribed medicine for, chronic pain to participate in a study investigating ways to better address problems with chronic pain and prescription pain medication. Participants met study inclusion criteria if they reported chronic noncancer pain on more days than not and had taken opioid analgesics daily or nearly every day for at least the past 90 days. In the combined sample (see Table 1 for demographic and clinical characteristics), participant average duration of opioid use was 10.13 ± 7.17 years, and at baseline, the mean score on the COMM was 11.64 ± 7.68; thus, on average, this was an opioid misusing sample, insofar as participants exhibited mean COMM scores that surpassed a clinically validated cutpoint indicating opioid misuse (COMM ≥ 9) (37). Participants were excluded if they had engaged in previous mindfulness-based intervention or were actively suicidal or psychotic as determined by the Mini-International Neuropsychiatric Interview 6.0 (38). Research procedures were approved by the University of Utah Institutional Review Board. Participants gave their written informed consent, could withdraw from the study at any time, and were financially compensated. Experiment 1 evaluated EEG data from a mechanistic study of civilian chronic prescription opioid users (n = 40). Experiments 2 and 3 evaluated EEG data from a mechanistic study of U.S. military veterans who were chronic prescription opioid users (n = 31). In this study, several participants were missing pre- or posttreatment data due to hardware problems or inability to continue the assessment due to chronic pain; consequently, the analysis n for experiment 2 was 24, whereas the analysis n for experiment 3 was 29. Experiment 4 evaluated affect and craving ratings from a cue-reactivity task deployed as part of a mechanistic aim from a recently completed stage 2 RCT of civilian chronic prescription opioid users. Individuals with data from this mechanistic task (n = 64) were included in the present investigation. Experimental design All four experiments used a randomized controlled pretest-posttest design. At pre- and posttreatment assessments, participants completed a laboratory-based cue-reactivity task (described below). In experiments 1 to 3, EEG was recorded during the task. In experiment 4, self-reported affect and craving ratings were obtained during the task. In experiment 4, participants were also assessed with the COMM (38), a validated measure of opioid misuse risk, at pretreatment and again at 3-month follow-up. Across all four experiments, following the pretreatment assessment, participants were randomly assigned by a project staff member who was uninvolved with assessment or treatment to an 8-week MORE group or SG. Random assignment occurred via a computerized random number table generated by a researcher who was uninvolved in assessment, treatment, or enrollment using simple randomization in blocks of varying sizes (two to four) to preserve unpredictability of allocation. The allocation list was stored in a protected file inaccessible to project staff involved in assessment or treatment. Assessments were conducted by project staff blinded to group assignment (which remained concealed throughout the study). Before each assessment, participants were reminded to not disclose their group assignment to study staff to ensure blinding of study personnel. Study interventions Participants were randomly assigned to receive eight weekly sessions of MORE or eight weekly sessions of a therapist-led SG control condition. MORE sessions involved mindfulness training to cultivate self-awareness, cognitive control, and self-transcendence; reappraisal training to facilitate emotion regulation; and training in savoring pleasant events and emotions to enhance natural reward processing and positive affectivity. Per the MORE treatment manual (39), session topics focused on applying mindfulness, reappraisal, and savoring skills to reduce addictive tendencies toward opioids (including opioid cue-reactivity) and promote responsiveness to natural rewards. Mindfulness skills involved mindful breathing and body scan techniques. In MORE, participants were instructed to cultivate mindful awareness of automaticity in the context of opioid use and to shift attention to the sensations of breathing as a means of interrupting automatic, habitual, and compulsive use of opioids. When craving arises during this process, participants were instructed to use mindfulness to deconstruct it into its cognitive, emotional, and sensorial components while metacognitively monitoring these mental phenomena from a psychological distance. Next, participants were instructed to reappraise the meaning of the craving by contemplating the consequences of indulging the craving versus remaining abstinent. Last, participants were instructed to use mindfulness to shift attention away from drug cues and cravings and toward the pleasurable features of naturally rewarding, salutary objects and events as a means of savoring the positive emotions and sensations that arise in response to pleasant life experiences. Participants were also asked to engage in daily 15-min mindfulness, reappraisal, and savoring practice sessions at home guided by an audio recording. In addition, participants were asked to engage in 3 min of mindful breathing before making a decision about whether to take their next opioid dose. This exercise was intended to increase awareness and self-regulation of opioid cue-reactivity. Group sessions were 2 hours long and led by a master’s-level clinical social worker. The manualized active SG control condition in this study consisted of eight weekly, 2-hour SG sessions, in which a master’s-level social worker facilitated emotional expression and discussion of topics pertinent to chronic pain and opioid use/misuse. This Rogerian, client-centered SG format was based on the evidence-based matrix model intensive outpatient treatment manual and validated as a control condition in a stage 2 RCT of MORE (25). SG participants were asked to engage in 15 min of journaling a day on chronic pain–related themes. To prevent treatment diffusion, participants in the SG condition were instructed to not engage in mindfulness training during the course of the study. A licensed clinician with over 15 years of experience conducted clinical supervision and reviewed session audio recordings to monitor therapist adherence to the MORE and SG treatment manuals and maintain intervention fidelity. Assessment of opioid cue-reactivity In experiments 1 and 2, while EEG was recorded (see the “Electrophysiological recordings” section below), participants were presented with opioid and neutral cues. On each trial, participants were first shown a fixation cross for 500 ms, followed by 250- to 500-ms jittered blank screen and then an image and instruction label for 6000 ms. In experiment 1, two opioid cue blocks and one neutral cue block each composed of 40 trials were presented in counterbalanced order, with neutral blocks presented in between opioid blocks, to maximize sensitivity to detect the effects on cue-reactivity. Before formal analyses to test our primary hypothesis in experiment 1 that MORE could affect opioid cue-reactivity, we first tested whether the effects of MORE on the LPP differed on view versus regulate blocks. Treatment groups differed by time on LPP response to neutral versus both opioid cue conditions (P = 0.03), but view and regulate strategies did not significantly differ from one another (P = 0.96). Therefore, our primary analysis in experiment 1 collapsed across all opioid trials to focus on the Group (MORE versus SG) × Time (Pretreatment versus Posttreatment) × Stimulus (Neutral versus Opioid) interaction. In experiment 2, 48 opioid trials were presented in a randomized event-related design to maximize sensitivity to detect the effects of conscious down-regulation (regulate < view) of neurophysiological responses to opioid cues on a trial-by-trial basis. In experiment 2, significant differences between view and regulate strategies were observed and reported above. Participants were instructed to view or regulate responses to the stimuli. On view trials, participants were instructed to simply attend to images of opioid pills and pill bottles validated in previous studies (27) or neutral images (e.g., household objects) whose basic visual properties were matched to the opioid cues. At baseline, opioid images were rated to be significantly more arousing than neutral images (P = 0.02), providing a manipulation check and demonstrating the validity of the stimuli used in our experimental paradigm. On regulation trials, participants were instructed to observe the image while maintaining nonreactive, nonjudgmental awareness of their thoughts, emotions, and body sensations—using a mindfulness strategy to down-regulate their response to the opioid image. In a training session before EEG assessment, participants practiced this regulatory strategy and described their experience to a trained research assistant to ensure comprehension of the instructions. EEG assessment did not commence until participants could accurately describe implementation of regulatory instruction. Assessment of natural reward responsiveness In experiments 3 and 4, participants were presented with images representing natural rewards. On each trial, participants were first shown a fixation cross for 500 ms, followed by 250- to 500-ms jittered blank screen and then an image and instruction label for 6000 ms. In experiment 3, 32 natural reward trials were presented in a randomized event-related design to maximize sensitivity to detect the effects of conscious up-regulation (regulate > view) of neurophysiological responses to natural reward cues on a trial-by-trial basis. In experiment 4, two natural reward cue blocks (regulate versus view) each composed of 40 trials were presented in counterbalanced order. Participants were instructed to view or regulate responses to stimuli. On view trials, participants were instructed to simply attend to images of naturally rewarding stimuli (e.g., social affiliation, natural beauty, and athletic victories) validated in previous studies (33). On regulate trials, to approximate mindful savoring techniques and conform with typical “increase positive” instructions on emotion regulation tasks (24), participants were instructed to imagine experiencing the positive event occurring in the image and to focus on enjoyable aspects of the image and their own positive emotional response to the image. As above, in a training session before EEG assessment, participants practiced this regulatory strategy and described their experience to a trained research assistant to ensure comprehension of the instructions. EEG assessment did not commence until participants could accurately describe implementation of regulatory instruction. In experiment 4, at baseline and then after each task block, participants rated their current positive affective state from 1 (not positive at all) to 4 (extremely positive), as well as their current opioid craving from 1 (no craving) to 4 (extreme craving). Self-reported affect and craving ratings were skewed and subsequently log-transformed before analysis. Reactivity scores were computed by subtracting self-reported affect and craving ratings at baseline from ratings following task blocks. These reactivity scores were entered into RM-ANOVA models for analysis. Electrophysiological recordings EEGs were continuously recorded using a 32-channel active sensor cap with Ag/AgCl electrodes (actiCap GmbH, Herrsching, Germany). In addition, electro-oculograms (EOG) of vertical eye movements were recorded using actiCHamp sensors (Brain Products GmbH, Gilching, Germany). All recordings were collected using an actiCHamp amplifier and BrainVision Recorder software (version 1.21.0004, Brain Products GmbH, Germany). Data were acquired at a sampling rate of 500 Hz, a resolution of 0.489 μV, and a hardware amplification cutoff of 140 Hz. Electrophysiological preprocessing Data from the Cz and Pz midline electrode sites were averaged to compute the centroparietal LPP. Offline processing rereferenced EEG channels with a TP11 mastoid reference/TP9 linked ear clips in BrainVision Analyzer 2.1.2.327 (Brain Products GmbH, Germany). Next, a low cutoff filter of 0.1 Hz, a high cutoff filter of 40 Hz, and a notch filter of 60 Hz were applied offline. Independent component analysis (ICA), specifically a fast ICA restricted algorithm, was executed to semiautomatically remove ocular artifacts from EEG channel recordings. Tasks were segmented and then blocked by trial type for further processing. Artifact rejection was semiautomatic with parameters set as follows: maximal allowed voltage step of 50 μV/ms; maximal allowed absolute difference of values in intervals: 200 μV with a 200-ms interval length; lowest allowed activity in intervals: 0.5 μV with an interval length of 100 ms. All intervals contaminated with muscle, ocular, or non-neuronal electrical activity were marked 200 ms before and after stimulus presentation and removed. Program-flagged artifacts were inspected manually for artifacts. Nine percent of trials were rejected for artifacts in experiment 1, whereas 19% of trials in experiment 2 and 24% of trials in experiment 3 were rejected for artifacts. ERP grand average waveforms were generated separately for each condition, referenced to a 150-ms prestimulus baseline preceding image onset. To isolate LPP maxima, we examined the morphology of the waveforms in the present study and followed conventions from previous research to define the LPP time window. In experiment 1, we examined the LPP from 400- to 800-ms poststimulus presentation to capture the maximal LPP peak known to be modulated during reactivity to emotionally salient cues (8, 13). In experiment 2, we examined the LPP from 400 to 1000 ms to capture the effects of attention regulation via mindfulness; attention regulation strategies are known to operate between 700 and 900 ms (14). In experiment 3, we examined the LPP from 400 to 1500 ms to capture the effects of evaluative emotion regulation via savoring; evaluative emotion regulation strategies are known to operate as late as 1500 ms (14). The LPP was scored by computing mean activity in microvolts in these windows on each trial. Statistical analyses were conducted on signal-averaged LPP data. Statistical analysis Effects of treatment on the signal-averaged LPP response and subjective responses were examined using RM-ANOVA. To ensure the success of our randomization procedure, we first tested whether there were group differences at pretreatment in LPP response. No significant between-groups differences in pretreatment LPP response were observed in experiment 1 (F 1,38 = 0.02, P = 0.89, η partial 2 < 0.01), experiment 2 (F 1,22 = 0.06, P = 0.81, η partial 2 < 0.01), or experiment 3 (F 1,27 = 1.29, P = 0.27, η partial 2 = 0.05). We performed a power analysis under a range of possible effect sizes and RM correlations. For instance, assuming a small-medium effect size (Cohen’s f = .25) and a medium RM correlation (r = 0.35), power for the signal-averaged LPP analysis is 0.80 with n = 43. With a Cohen’s f = 0.30 and a large RM correlation (r = 0.50), statistical power is 0.83 with n = 26. In contrast, assuming a medium-large effect size (Cohen’s f = 0.35) and a medium RM correlation (r = 0.35), statistical power is 0.82 with n = 24. This latter effect size estimate was based on effect sizes observed in three published studies of the effects of MORE on cardiac autonomic reactivity (η partial 2 = 0.18) (28), LPP responses (η partial 2 = 0.17), and BOLD responses in striatal reward circuitry (Cohen’s d = 2.13) (29) to natural reward cues. Our actual observed effect size in experiment 1 (Cohen’s f = 0.37) was close to the latter assumption, yielding an achieved power of 0.95. For hypothesis testing, in experiment 1, we assessed the interaction of Group (MORE versus SG) with Time (Pretreatment versus Posttreatment) and Stimulus Type (Opioid versus Neutral) on LPP response. In experiments 2 and 3, we assessed the interaction of Group (MORE versus SG) with Time (Pretreatment versus Posttreatment) and Condition (View versus Regulate) on LPP response. When appropriate, Greenhouse-Geisser corrected values were used, and significant (P < 0.05) main effects and interactions were interrogated with Bonferroni-adjusted planned post hoc tests. RM-ANOVA models of LPP response included posttreatment opioid dose (in average daily morphine equivalents) to control for the pharmacological impact of opioid exposure on electrocortical responses. In a separate series of sensitivity analyses, we controlled for pain severity, and effects of MORE on LPP responses in experiments 1 to 3 remained statistically significant. Because of the small sample size in experiments 2 and 3, we used multilevel modeling (MLM) of trial-level LPP data as an additional sensitivity analysis for these two experiments. Given its capacity to partition sources of variance from the error term, MLM increases power to detect fixed effects without averaging across trials to minimize noise, and thus, this analytic technique is seen as well suited for application to ERP research (40). MLM models included random intercepts and no random slopes. Change in model fit statistics (i.e., −2LL) was used to select the optimal covariance structure for repeated effects (e.g., AR1 versus diagonal) as well as for our overall model building approach. We began parsimoniously by first examining an unconditional growth model and then adding fixed effects and evaluating model fit with likelihood ratio tests. Satterthwaite approximations estimated degrees of freedom. In experiment 2, the significant likelihood ratio test (χ2 diff = 17.87, df diff = 6, P = 0.006) indicated that the fully parameterized model should be retained over the unconditional growth model, and the Group × Time × Condition interaction was significant in trial-level MLM analyses (F 1,1473.29 = 5.49, P = 0.019). In experiment 3, the significant likelihood ratio test (χ2 diff = 22.04, df diff = 6, P = 0.001) indicated that the fully parameterized model should be retained over the unconditional growth model, and the significant likelihood ratio and the Group × Time × Condition interaction were also significant in trial-level MLM analyses (F 1,1034.53 = 6.25, P = 0.013). We then computed a measure of relative responsiveness to natural reward versus drug reward by subtracting LPP regulatory response to opioid cues from LPP regulatory response to natural reward cues (regulate − view difference scores) and assessed the Group × Time interaction on this relative responsiveness measure. This analytic approach has been used in previous LPP studies of individuals with substance use disorders (17). Our statistical plan for this approach was modeled from a previous study of MORE in which we identified a significant Group × Time interaction on an autonomic measure of relative responsiveness to natural reward versus drug reward (35). In experiment 4, we assessed the interaction of Group (MORE versus SG) with Time (Pretreatment versus Posttreatment) and Condition (View versus Regulate) on log-transformed positive affect and craving reactivity scores (task block ratings − baseline ratings). Last, in experiment 4, we conducted a path analysis with bootstrapping in PROCESS 2.16.1 software to evaluate pre-post changes in subjective natural reward responsiveness as a mediator of treatment effects (MORE versus SG) on changes in opioid misuse (as measured by the COMM) from pretreatment to 3-month follow-up, with significant mediation indicated by the 95% bias-corrected confidence intervals not spanning zero.
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Acknowledgments: Funding: Data analysis and manuscript preparation were supported by grant numbers R01DA042033 and R61AT009296 from the NIH (principal investigator: E.L.G.), W81XWH-15-PRMRP-CTA from the Department of Defense (principal investigator: E.L.G.), and a grant from the Fahs Beck Fund for Research and Experimentation (principal investigator: E.L.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Author contributions: E.L.G. conceptualized the study, spearheaded manuscript preparation, and performed statistical analyses. R.M.A. processed the neurophysiology data and computed ERP grand averages. A.W.H. processed mindfulness practice data and analyzed associations between practice and reward-related processes. E.L.G., B.F., R.M.A., J.-K.Z., and A.W.H. assisted in interpretation of the data, helped in the literature review, and participated in the drafting of the manuscript. All authors have approved the final article. Competing interests: E.L.G. is the Director of the Center on Mindfulness and Integrative Health Intervention Development. The Center provides MORE, mindfulness-based therapy, and cognitive behavioral therapy in the context of research trials for no cost to research participants; however, E.L.G. has received honoraria and payment for delivering seminars, lectures, and teaching engagements (related to training clinicians in MORE and mindfulness) sponsored by institutions of higher education, government agencies, academic teaching hospitals, and medical centers. E.L.G. also receives royalties from the sale of books related to MORE. J.-K.Z. is a consultant of, and received consultant fees from, Alkermes Inc. for work unrelated to the content of the manuscript. The other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper. Additional data related to this paper may be requested from the authors. |
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1. Introduction {#sec1-materials-12-02567}
===============
The BCL-2 family of proteins forms a complex protein-protein interaction (PPI) network that regulates cellular life and death decisions, which contributes to organismal development, cancer ontogeny and chemoresistance, hematopoiesis, and immune regulation \[[@B1-materials-12-02567],[@B2-materials-12-02567],[@B3-materials-12-02567],[@B4-materials-12-02567]\]. Members of the BCL-2 family known as BH3-only proteins (e.g., BIM, BID, PUMA, NOXA) serve as cellular stress sentinels and can trigger irreversible activation of apoptosis through their α-helical BH3 death domains. These pro-apoptotic signals are normally held in check by the multidomain anti-apoptotic family members (e.g., BCL-XL, BCL-2, BCL-W, MCL-1) through sequestering PPIs. However, when pro-apoptotic signals outweigh anti-apoptotic signals, the multidomain pro-apoptotic effectors, BAX and BAK, are activated and trigger the cell death cascade by oligomerizing in the mitochondrial membrane, leading to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome formation, and effector caspase activation \[[@B1-materials-12-02567]\].
The BCL-2 family's PPIs have emerged as an impactful set of therapeutic targets \[[@B5-materials-12-02567]\]. Cancer cells often push the BCL-2 family's PPI balance toward an anti-apoptotic state to avoid cell death despite cellular stress and damage, for example by upregulating anti-apoptotic members or downregulating pro-apoptotic members \[[@B5-materials-12-02567],[@B6-materials-12-02567]\]. As most chemotherapies function by ultimately inducing apoptosis, cancers often acquire chemotherapeutic resistance by manipulating the homeostatic balance of BCL-2 family members \[[@B6-materials-12-02567]\]. BH3-mimetics are a powerful way to therapeutically interrupt this balance and reactivate cell death, particularly in cancers that are "primed for death" with upregulated anti-apoptotic proteins \[[@B7-materials-12-02567]\].
While intracellular PPIs are commonly deemed undruggable targets, peptides can effectively mimick the PPI interface domains of proteins and thus disrupt PPIs with high specificity and affinity. However, because peptides are typically not cell permeable, chemical poration of the cell membrane is required for peptides to reach their intracellular targets, making many potential peptides irrelevant for therapeutic applications. Hydrocarbon-stapled peptides are a noteworthy exception in which an all-hydrocarbon staple is installed across helical turns of a peptide. These stapled peptides have enhanced α-helicity, resist proteolysis, and, with empirical screening, can be made cell-permeable \[[@B8-materials-12-02567],[@B9-materials-12-02567],[@B10-materials-12-02567]\].
Recent work has shown that peptide amphiphiles (PAs), or peptides linked to a hydrophobic, lipid-like tail, can also impart cellular uptake for otherwise cell-impermeable peptides \[[@B11-materials-12-02567],[@B12-materials-12-02567],[@B13-materials-12-02567]\]. Moreover, these PAs can spontaneously self-assemble into micellar nanostructures in aqueous solution. Supramolecular peptide delivery provides several advantages compared to peptides alone: single micelles can (1) deliver high concentrations of peptides into cells; (2) stabilize peptide secondary structure(s); (3) protect peptides from proteolysis in the blood stream; (4) increase circulation half-lives; and (5) simultaneously deliver multiple therapeutics targeting non-redundant, synergistic cellular pathways \[[@B14-materials-12-02567]\]. We have also previously shown that PA micelles can be actively targeted to specific cell types in vivo, where a targeting PA can successfully carry non-targeted cargo to a target receptor simply through their supramolecular co-assembly \[[@B15-materials-12-02567],[@B16-materials-12-02567]\].
While the exact mechanism of PA cellular uptake remains unproven, recent work has shown that PAs interact with the cell membrane and traffic through endosomes and lysosomes \[[@B11-materials-12-02567],[@B12-materials-12-02567],[@B13-materials-12-02567],[@B17-materials-12-02567]\]. However, facile intracellular delivery and the release from endosomal/lysosomal compartments have been significant limitations to using PAs for intracellular delivery of biofunctional peptides. We recently showed that incorporating an endosomally-cleavable linker between the peptide cargo and lipid tail enhances intracellular accumulation and minimizes lipid-driven recycling out of the cell \[[@B18-materials-12-02567]\].
Here, this study develops and biochemically characterizes novel PAs able to intracellularly deliver an α-helical peptide mimicking the BH3 death domain of BIM previously shown to bind BCL-2 family members and potently reactivate apoptosis in resistant malignancies \[[@B19-materials-12-02567],[@B20-materials-12-02567],[@B21-materials-12-02567],[@B22-materials-12-02567]\]. In so doing, these PAs overcome membrane sequestration, plasma membrane recycling, and lysosomal degradation limitations known to decrease the potency of first-generation PAs. Using native peptides, which by themselves are cell-impermeable, the BIM BH3 domain was attached to hydrophobic tails and thereby incorporated into spherical micelles, which are ideal for in vivo delivery and trafficking \[[@B23-materials-12-02567]\]. Lastly, intracellular organelle sequestration of the biofunctional peptide was overcome through the incorporation of a cathepsin-cleavable linker between the peptide and hydrophobic tail.
2. Materials and Methods {#sec2-materials-12-02567}
========================
2.1. Micelle Synthesis {#sec2dot1-materials-12-02567}
----------------------
Two overlapping but functionally non-equivalent sequences of the BCL-2 binding motif of the BIM protein (BIM~A~: IWIAQELRRIGDEFNAYYARR \[[@B19-materials-12-02567]\], and BIM~B~: MRPEIWIAQELRRIGDEFNA \[[@B24-materials-12-02567],[@B25-materials-12-02567]\]) were synthesized on 0.25 mmoles of rink amide resin (Novabiochem) through standard Fmoc-mediated solid phase peptide synthesis methods using an automated PS3 Benchtop Peptide Synthesizer (Protein Technologies, Tucson, AZ, USA). Amino acids were used in 4X excess. Each coupling began with Fmoc-deprotection of the resin using 20% piperidine in dimethylformamide (DMF), followed by amino acid activation with N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 0.4 M N-methylmorpholine in DMF before adding the activated amino acid to the resin. Five lysines were added at the C-termini of both sequences to make them more charged and water-soluble. After splitting each batch of the peptides in half, one half was acetylated with acetic anhydride in DMF, while the other half was labeled with fluorescein isothiocyanate (FITC; Molecular Probes) at their N-termini. The acetylated and FITC-labeled peptides were again each divided in half. One half was conjugated at the ε-amine of C-terminal lysine to dipalmitoylglutamic acid, or diC16, as described previously \[[@B18-materials-12-02567],[@B26-materials-12-02567]\] to form Ac-BIM-PA~1~ or FITC-BIM-PA~1~. The other half was coupled with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-\[succinyl(polyethylene glycol)-2000\], or DSPE-PEG(2000)-succinyl (Avanti Polar Lipids, Alabaster, AL, USA), using equal molar equivalent of peptide to lipid in a 1:1 mixture of DMF:DCM and named Ac-BIM-PA~2~ or FITC-BIM-PA~2~. The same peptides were re-synthesized with a cathepsin cleavage sequence---Valine, Citrulline (VCit)---incorporated between the BIM sequences and the five C-terminal lysines, and the modified PAs were named Ac-BIM~cath,K~PA~2~ or FITC-BIM~cath,K~PA~2~. Peptide amphiphiles were then cleaved with 82.5:5:5:2.5 by volume trifluoroacetic acid: H2O: phenol: thioanisole: 1,2-ethanedithiol. They were precipitated and washed with cold diethyl ether, dried under nitrogen, and dissolved in water. Reverse-phase HPLC (Prominence, Shimadzu, Columbia, MD, USA) on a C8 column (Waters, Milford, MA, USA) at 40 °C was employed to purify soluble peptides using a gradient method and acetonitrile/water solvents containing 0.1% formic acid. The fractions were mass-characterized by MALDI-TOF mass spectral analysis (Biflex III, Bruker, Billerica, MA, USA) and the confirmed fractions were aliquoted, lyophilized, and stored as powders at −20 °C ([Figures S1,S2](#app1-materials-12-02567){ref-type="app"}). The exact concentrations of the aliquots were determined by amino acid analysis (AAA). To fabricate BIM micelles, the lyophilized powders were reconstituted, sonicated for 1 h at room temperature, incubated in 70 °C water bath for 1 h, and left at room temperature for at least 2 h to cool down and equilibrate.
2.2. Critical Micelle Concentration (CMC) {#sec2dot2-materials-12-02567}
-----------------------------------------
To measure the CMC of PA micelles, 1,6-diphenyl-1,3,5-hexatriene (DPH) was first dissolved in tetrahydrofuran and then diluted in water to 1 μM final concentration. A range of PA solutions (from 512 μM to 0.01 μM in serial one-half dilutions) were prepared in a 1 μM DPH solution and left to equilibrate for 1 h at room temperature. These solutions were plated in triplicates in a 96-well plate, and their fluorescence intensity was measured using a Tecan Infinite 200 plate reader (Mannedorf, Switzerland). DPH was excited at 350 nm, and fluorescence emission was measured at 428 nm. The concentration values were log transformed, and the data were fit with a trend line for the increasing intensity measurements. The CMC relies on the partitioning of DPH from the aqueous solution into the hydrophobic core of intact PA micelles, resulting in a sharp increase in fluorescence intensity. The CMC was calculated as the inflection point where the fluorescence intensity began to increase.
2.3. Dynamic Light Scattering (DLS) {#sec2dot3-materials-12-02567}
-----------------------------------
Stock solutions of 0.5 mM BIM PAs were prepared as mentioned above, and DLS measurements were performed at a 90° angle with a 637 nm laser using a Brookhaven Instruments (Holtzville, NY, USA) system with a BI-9000AT autocorrelator. Hydrodynamic radii were determined via the Stokes-Einstein equation using the diffusion coefficient determined from the auto correlation function.
2.4. Transmission Electron Microscopy (TEM) {#sec2dot4-materials-12-02567}
-------------------------------------------
Ultrathin carbon type-A 400 mesh copper grids (Ted Pella, Redding, CA, USA) were loaded with 1 μL of BIM PAs and allowed to dry. The grids were washed with several drops of water and then negatively stained with 1% aqueous phosphotungstic acid for 1 min. The excess solution was then removed and grids were left to dry. All the grids were imaged on a FEI Tecnai 12 TEM (Hillsboro, OR, USA) using an accelerating voltage of 120 kV.
2.5. Circular Dichroism {#sec2dot5-materials-12-02567}
-----------------------
A quartz cuvette with a 0.1 cm pathlength was loaded with 200 μL of 50 μM solutions of BIM PAs. Measurements were done at 25, 37, 42 and 50 °C with a Jasco J-815 Circular Dichroism Spectropolarimeter (Easton, MD, USA). Each sample was scanned five times from 250 to 190 nm, and the data were averaged. Mean residue ellipticity \[θ\] was calculated using Equation (1): with units degree x cm^2^ x dmol^−1^ x residue^−1^. Percent alpha-helicity was then calculated from the value of \[θ\] at 222 nm using Equations (2) and (3):$$\%\ Helicity\ = \ 100 \times \left\lbrack \mathsf{\theta} \right\rbrack_{222}\ /\ \lbrack\mathsf{\theta}\rbrack\ _{222}^{max}\ {where}$$ $$\lbrack\mathsf{\theta}\rbrack\ _{222}^{max} = - 40,000 \times \left\lbrack {1 - \left( {2.5/amino\ acid\ residues} \right)} \right\rbrack + 100 \times T$$ with *T* measured in °C \[[@B27-materials-12-02567],[@B28-materials-12-02567]\].
2.6. Lactate Dehydrogenase Release Assay {#sec2dot6-materials-12-02567}
----------------------------------------
Mouse embryonic fibroblasts (MEFs) were cultured in a 96-well plate (5000 cells per well) and allowed to adhere overnight. A serial dilution of the BIM PAs (25, 12.5, 6.25, 3.125, and 1.563 μM) as well as 1% triton were prepared in treatment media (Advanced DMEM, 1% FBS, 0.1% penicillin/streptomycin), and the cells' media was replaced with the treatment dilutions to a final volume of 100 μL in each well. After incubation at 37 °C for 1 h, 50 μL of the treatment media was removed carefully from each well, transferred to a new plate, and mixed with 50 μL of lactate dehydrogenase (LDH) reagent (Roche) for 30 min while shaking, and absorbance was then measured at 492 nm on a microplate reader (SpectraMax M5 Microplate Reader, Molecular Devices, San Jose, CA, USA).
2.7. Protein Production {#sec2dot7-materials-12-02567}
-----------------------
Recombinant and tagless BCL-XLΔC, MCL-1ΔNΔC, BCL-2ΔC and BCL-WΔC were produced and purified as described previously \[[@B19-materials-12-02567]\]. Briefly, glutathione-S-transferase fusion proteins were expressed in Escherichia coli BL21 (DE3) using pGEX2T (Pharmacia Biotech) constructs. Bacterial cells were cultured in ampicillin-containing Luria Broth, and protein expression was induced with 0.5 mM isopropyl β-D-1-thiogalactopyranoside. The bacterial pellet was resuspended in PBS containing 1 mg/mL lysozyme, SigmaFAST protease inhibitor tablet (Sigma-Aldrich, St. Louis, MO, USA), and 1% (*v*/*v*) Triton X-100. Bacteria were lysed by sonication at 4 °C, and, after centrifugation at 16,000× *g* for 30 min, the supernatant was applied to a glutathione-agarose (Sigma-Aldrich, St. Louis, MO, USA) column and washed with PBS. Tagless protein was obtained by overnight on-bead digestion with 50 units of thrombin (GE Healthcare, Pittsburgh, PA, USA) in 3 mL PBS at room temperature. The cleaved proteins were purified by size exclusion chromatography using 150 mM NaCl and 50 mM Tris (pH 7.4) buffer conditions on a Superdex-75 gel filtration column (GE Healthcare, Pittsburgh, PA, USA).
2.8. Fluorescence Polarization (FP) Binding Assay {#sec2dot8-materials-12-02567}
-------------------------------------------------
FP binding assays were performed as previously described \[[@B19-materials-12-02567],[@B29-materials-12-02567]\]. FITC-labeled peptides and peptide amphiphiles (50 nM) were incubated with serial dilutions of recombinant protein in FP binding buffer (50 mM Tris, 100 mM NaCl, pH 8.0) until equilibrium was reached. FP was measured using a SpectraMax M5 microplate reader (Molecular Devices, San Jose, CA, USA). To calculate K~d~ values, the data were fitted to normalized sigmoidal curves with a variable slope using nonlinear regression analysis in Graphpad Prism.
2.9. Cathepsin B Cleavage FP and Fluorogenic Assays {#sec2dot9-materials-12-02567}
---------------------------------------------------
Cathepsin B purified from human liver (Sigma-Aldrich, St. Louis, MO, USA) was diluted 1:40 in cathepsin B activation buffer (25 mM HEPES, 25 mM DTT, pH 5.0) and incubated at room temperature for 15 min to activate the enzyme. FITC- BIM~A,cath,K~PA~2~ was added to activated enzyme to achieve a final peptide amphiphile concentration of 50 μM and incubated at room temperature for 30 min. The reaction was stopped by diluting the reaction mixture 1:100 in FP binding buffer (50 mM Tris, 100 mM NaCl, pH 8.0). The enzyme-treated peptide amphiphile (50 nM) was then incubated with serial dilutions of recombinant protein in FP binding buffer until equilibrium was reached. FP was measured using a SpectraMax M5 microplate reader (Molecular Devices, San Jose, CA, USA), and K~d~ values were calculated as described above.
The fluorogenic cathepsin-cleavage assay was done as previously described \[[@B18-materials-12-02567]\] using the cathepsin B cleavage substrate Z-Arg-Arg-7-amido-4-methylcoumarin hydrochloride (Z-RR-AMC; Sigma-Aldrich, St. Louis, MO, USA) and human cathepsin B with or without the cathepsin inhibitor CA-074Me (EMD Millipore, Burlington, MA, USA).
2.10. Cell Culture {#sec2dot10-materials-12-02567}
------------------
Mouse embryonic fibroblasts (MEFs) and HeLa cells were maintained in DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 10% FBS, 100 U/mL penicillin/streptomycin, 2 mM L-glutamine, and 0.1 mM MEM nonessential amino acids.
2.11. Live Cell Confocal Microscopy {#sec2dot11-materials-12-02567}
-----------------------------------
HeLa cells were incubated with 10 μM FITC-labeled peptides or PAs for the indicated time in Advanced DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 1% FBS. The media was then removed, and the cells were washed and then incubated in prewarmed Opti-MEM (Invitrogen, Carlsbad, CA, USA) containing 250 nM MitoTracker Red (Invitrogen, Carlsbad, CA, USA) and 5 μg/mL Hoechst 33342 (Invitrogen, Carlsbad, CA, USA) for 30 min. The cells were then washed and incubated in Opti-MEM media lacking phenol red (Invitrogen, Carlsbad, CA, USA). Confocal images were collected on an Olympus DSU spinning disk confocal system (Olympus, Carlsbad, CA, USA) with a heated platform and a humidified chamber with 5% CO~2~. Excitation of the 3 fluorophores was performed sequentially using 405-nm, 488-nm, and 561-nm lasers. Images were acquired using a 100 Plan Apo objective lens with a Hamamatsu EM-CCD camera (Andor Technology, Belfast, UK). Acquisition parameters, shutters, filter positions, and focus were controlled by Slidebook 6 software (Intelligent Imaging Innovations, Denver, CO, USA).
2.12. Cell Viability Assay {#sec2dot12-materials-12-02567}
--------------------------
MEF cells were aliquoted (2.5 × 10^3^, 100 μL) in 96-well opaque plates in complete DMEM media, and, 24 h later (at 75%--90% cellular confluence), the media was removed. The indicated doses of peptides or PAs were then added in Advanced DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 1% FBS, and after 6 h of treatment, 10% FBS was added back to the media. Cell viability was measured at the indicated time points by the addition of CellTiter-Glo chemiluminescence reagent in accordance with the manufacture's protocol (Promega, Madison, WI, USA). Luminescence was detected by a Synergy 2 microplate reader (BioTek Instruments, Inc., Winooski, VT, USA).
2.13. Caspase-3/7 Activation Assay {#sec2dot13-materials-12-02567}
----------------------------------
Cells were treated as described above for the cell viability assays, and caspase-3/7 activation was measured at indicated time points by addition of the Caspase-Glo 3/7 chemiluminescence reagent in accordance with the manufacturer's protocol (Promega, Madison, WI, USA). Luminescence was detected by a Synergy 2 microplate reader (BioTek Instruments, Inc., Winooski, VT, USA). Caspase-3/7 activation per living cells was determined by the ratio of Caspase-Glo luminescence to the percent viability from the corresponding CellTiter-Glo assay from identical experiments plated simultaneously, as previously described \[[@B30-materials-12-02567]\].
2.14. Western Blotting {#sec2dot14-materials-12-02567}
----------------------
Treated MEFs were collected and lysed in lysis buffer (50 mM Tris, 150 mM NaCl, 1 mM EDTA, 1 mM DTT, 1% \[*v*/*v*\] Triton X-100, complete protease inhibitor tablet \[Roche\], pH 7.4; PBST), and the protein content of each lysate was quantified using BCA kit (Thermo-Fischer Scientific, Waltham, MA, USA). Further, 5 μg of total protein from each lysate was loaded and separated on a 12% SDS-PAGE gel, transferred onto a PVDF membrane, and blocked with 5% skim milk in PBST for 45 min. The membranes were probed with primary antibody overnight at 4 °C with antibodies against PARP (Cell Signaling, Danvers, MA, USA; 1:1000) and GAPDH (Santa Cruz, Dallas, TX, USA; 1:1000), followed by 1 h of incubation at room temperature with HRP-conjugated secondary antibody (Santa Cruz, Dallas, TX, USA; 1:8000). Immuno-reactivity was visualized with a chemiluminescent detection kit (Amersham, Little Chalfont, UK).
2.15. Confocal Imaging after Cathepsin Inhibition {#sec2dot15-materials-12-02567}
-------------------------------------------------
MEFs were cultured on coverslips inside 6-well plates overnight. They were then pre-treated with either 5 μM CA-074Me (cathepsin inhibitor) or 0.1% DMSO in complete DMEM for 1 h. The media was replaced with Advanced DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 1% FBS and 10 μM FITC-labeled PAs, and the cells were incubated for 2 h. Hoechst (5 µg/mL) was added to the media 30 min before the end of the PA incubation. The treatment media was then removed, and the cells were washed and fixed immediately with 4% paraformaldehyde in PBS for 10 min at room temperature. The fixed cells were then washed, and the coverslips were mounted on glass slides before imaging. Confocal images were collected on Leica TCS SP2 AOBS Laser Scanning Confocal microscope. The acquisition parameters, shutters, filter positions, and focus were controlled by LCS Leica confocal software LASAF 2.7.3.9723 (Leica, Wetzlar, Germany).
3. Results {#sec3-materials-12-02567}
==========
3.1. Peptide Amphiphile Design {#sec3dot1-materials-12-02567}
------------------------------
To test our PA delivery strategy for therapeutic peptides, we constructed a set of PAs to mimic the BH3 death domain of BIM (BIM~A~ BH3; [Figure 1](#materials-12-02567-f001){ref-type="fig"}). However, this peptide sequence is sparingly soluble in water, so five C-terminal lysines were added to increase the charge and solubility of the peptide (BIM~A,K~) ([Figure 1](#materials-12-02567-f001){ref-type="fig"}a). This peptide was attached to two different lipid-based tails, both of which our group and others have previously used to deliver peptides into cells, to form BIM~A,K~PA~1~ and BIM~A,K~PA~2~ ([Figure 1](#materials-12-02567-f001){ref-type="fig"}b, [Figures S1 and S2](#app1-materials-12-02567){ref-type="app"}). The lipid tails were attached to the side chain of the C-terminal lysine of the BIM BH3 peptides. Finally, a cathepsin-cleavable linker was incorporated between the therapeutic peptide and the C-terminal lysines to form a cathepsin-cleavable PA, BIM~A,cath,K~PA~2~, which we hypothesized would allow for release of the peptide cargo following PA uptake into the cell.
3.2. PAs Enhance Cellular Uptake Without Non-Specific Membrane Disruption {#sec3dot2-materials-12-02567}
-------------------------------------------------------------------------
The ability of the PAs to deliver the BIM~A~ BH3 peptide into cells was tested next, as these lipid tails have previously been shown to facilitate cellular internalization \[[@B11-materials-12-02567],[@B12-materials-12-02567],[@B13-materials-12-02567]\]. To determine the extent of intracellular localization, HeLa cells were incubated in the presence of FITC-labeled peptides or PAs for 2 h followed by imaging using live cell confocal microscopy. Prior to imaging, the cells were washed to remove non-cell associated PAs. BIM~A,K~ peptide alone was not taken up into cells, but the addition of a diC16 tail (BIM~A,K~PA~1~) or a DSPE-PEG tail (BIM~A,K~PA~2~) enabled cell uptake of the otherwise cell-impermeable peptide ([Figure 2](#materials-12-02567-f002){ref-type="fig"}a). The DSPE-PEG PA, BIM~A,K~PA~2~, was more localized to the cellular membrane at this time point, while the diC16 PA, BIM~A,K~PA~1~, had a more diffuse intracellular presence. Importantly, both BIM~A,K~PA~2~ and BIM~A,cath,K~PA~2~ had greater presence at the membrane and in punctate organelles when compared to BIM~A,K~PA~1~, suggesting poorer penetrating ability of the DSPE-PEG tail compared to the diC16 tail. Incorporation of a hydrophilic PEG domain has previously been shown to affect membrane interactions and uptake mechanisms \[[@B13-materials-12-02567]\], with a PEG spacer causing cellular internalization more dependent upon the active uptake mechanisms. Interestingly, when a cathepsin-cleavable linker was added between the peptide and DSPE-PEG tail domain in BIM~A,cath,K~PA~2~, the intracellular peptide more quickly became diffuse and co-localized with mitochondria, the site of action of the BCL-2 family of proteins ([Figure S3](#app1-materials-12-02567){ref-type="app"}). This localization of BIM~A,cath,K~PA~2~ was observed to be time dependent ([Figure S4](#app1-materials-12-02567){ref-type="app"}).
As the proposed mechanism(s) of PA uptake involves interactions of the lipid domains with the cell membrane, it is critical to test for non-specific membrane disruption and cytotoxicity caused by the lipid tails \[[@B21-materials-12-02567]\]. To rule out non-specific membrane disruption, the release of cytoplasmic LDH from cells treated with PAs was measured 1 h following treatment ([Figure 2](#materials-12-02567-f002){ref-type="fig"}b). BIM~A,K~PA~1~, which readily entered the cells, caused dose-dependent LDH release, indicating some degree of non-specific lipid-associated membrane disruption. The DSPE-PEG tail of BIM~A,K~PA~2~, however, caused no measurable LDH release, with or without the cathepsin-cleavable linker ([Figure 2](#materials-12-02567-f002){ref-type="fig"}b). Based upon its facile intracellular penetration, lack of non-specific cellular membrane disruption, and ability to diffusely disseminate the BIM BH3 peptide, BIM~A,cath,K~PA~2~ appeared to be a logical candidate PA for further structural, target binding, and efficacy testing compared to BIM~A,K~PA~2~.
3.3. Biophysical Characterization of Micelles {#sec3dot3-materials-12-02567}
---------------------------------------------
The critical micelle concentration (CMC) was 1.04 μM and 1.54 μM for BIM~A,K~PA~2~ and BIM~A,cath,K~PA~2~, respectively ([Figure 3](#materials-12-02567-f003){ref-type="fig"}a). Dynamic light scattering (DLS) was used to measure the mean hydrodynamic radii (R~h~) of the micelles, which were 53.7 nm (±8.1 nm) for BIM~A,K~PA~2~ and 85.4 nm (±10.0 nm) for BIM~A,cath,K~PA~2~ ([Figure 3](#materials-12-02567-f003){ref-type="fig"}b). Imaging the micelles with negative-stain TEM confirmed the micelles were spherical, as expected for DSPE-PEG micelles, and the sizes agreed with the DLS measurements ([Figure 3](#materials-12-02567-f003){ref-type="fig"}c). Incorporation of a peptide into a micelle has been shown to increase its natural α-helical structure formation \[[@B31-materials-12-02567],[@B32-materials-12-02567],[@B33-materials-12-02567]\], so we next used circular dichroism (CD) to measure the alpha helicity of BIM~A,K~ after incorporation into micelles. BIM BH3 peptides within both PAs had similar degrees of alpha helicity, which were constant at temperatures ranging from 25 to 50 °C and after heating to 70 °C followed by cooling to 37 °C ([Figure 3](#materials-12-02567-f003){ref-type="fig"}d).
3.4. Target Protein Binding {#sec3dot4-materials-12-02567}
---------------------------
Specific apoptosis induction within cells requires selective binding of the BIM BH3 peptide to hydrophobic grooves formed by selective helical domains of anti-apoptotic and pro-apoptotic BCL-2 family target proteins \[[@B19-materials-12-02567],[@B21-materials-12-02567],[@B22-materials-12-02567],[@B34-materials-12-02567]\]. The addition of a large lipid tail, while facilitating intracellular delivery of BIM~A,K~PA~2~ and BIM~A,cath,K~PA~2~, may sterically inhibit the BIM BH3 peptide binding to its cognate target binding region. To test this, fluorescence polarization (FP) was used to measure the binding of FITC-labeled BIM BH3 peptides and PAs to recombinant antiapoptotic BCL-2 family proteins \[[@B19-materials-12-02567]\]. Indeed, the addition of a DSPE-PEG tail inhibited BIM~A,K~'s ability to bind to BCL-2, BCL-W, BCL-XL, and MCL-1 ([Figure 4](#materials-12-02567-f004){ref-type="fig"}a). The BIM~A,K~ peptide alone bound each protein with double-digit nanomolar affinity. However, the addition of the DSPE-PEG tail decreased these affinities by \~2--5 fold ([Figure 4](#materials-12-02567-f004){ref-type="fig"}a). Of note, BIM~A,K~ bound with affinities between 76--99 nM while BIM~A~ peptide (lacking the C-terminal lysines) is known to bind these same antiapoptotic targets with \~10× fold higher affinities, indicating that the addition of the lysines also likely dampened cognate target protein binding \[[@B19-materials-12-02567],[@B21-materials-12-02567],[@B35-materials-12-02567]\].
Based upon the intact PA:target protein binding affinities, we next aimed to determine if the release of the BIM BH3 peptide from both the C-terminal lysines and DSPE-PEG lipid tail could improve binding to BCL-2 family antiapoptotic protein targets. To do this, BIM~A,cath,K~PA~2~ was preincubated with recombinant cathepsin B enzyme prior to incubation with anti-apoptotic BCL-2 family proteins. Cathepsin pre-incubation resulted in time dependent increased affinities to BCL-XL plateauing between 15--30 min ([Figure 4](#materials-12-02567-f004){ref-type="fig"}b). Incubation of BIM~A,cath,K~PA~2~ with recombinant cathepsin for 30 min led to increased BIM BH3 peptide affinity for BCL-XL and MCL-1 ([Figure 4](#materials-12-02567-f004){ref-type="fig"}c). In fact, following the cleavage of the BIM BH3 native peptide from the C-terminal lysines and lipid tail, peptide affinity increased 6--10 fold compared to BIM~A,K~, presumably due to release from the C-terminal lysines (87 nM to 14 nM for BCL-XL and 99 nM to 10 nM for MCL-1) ([Figure 4](#materials-12-02567-f004){ref-type="fig"}c). These binding profiles reflect previously published reports of affinities of the BIM~A~ peptide for these proteins \[[@B19-materials-12-02567],[@B21-materials-12-02567]\]. These data suggest that following intracellular delivery of intact PAs, removing the lipid tail and C-terminal lysines from BIM~A~ is critical not only for the intracellular trafficking of the therapeutic peptide, but also for its ability to bind to its target proteins.
3.5. Cathepsin Dependence for Intracellular Accumulation {#sec3dot5-materials-12-02567}
--------------------------------------------------------
We next tested whether or not BIM~A,cath,K~PA~2~'s diffuse intracellular trafficking ([Figure 2](#materials-12-02567-f002){ref-type="fig"}a) depended on cathepsin cleavage of the BIM~A~ peptide from the DSPE-PEG tail by using cathepsin inhibitor CA-074Me. The cathepsin inhibitory effect of CA-074Me was first tested in vitro using recombinant cathepsin B added to a cathepsin-substrate linker that becomes fluorescent upon cathepsin cleavage ([Figure S5](#app1-materials-12-02567){ref-type="app"}). Cathepsin B caused a time-dependent increase in fluorescence while the addition of CA-074Me blocked reporter substrate cleavage.
To determine the importance of cathepsin cleavage on intracellular localization and trafficking of the BIM~A~ peptide, WT mouse embryonic fibroblasts (MEFs) were pre-treated with CA-074Me or a DMSO control for 1 h followed by incubation with 10 μM BIM~A,cath,K~PA~2~. In contrast to the more rapid intracellular localization of FITC-BIM~A,cath,K~PA~2~ in control-treated WT MEFs, those pre-treated with CA-074Me showed FITC-BIM~A,cath,K~PA~2~ localized primarily near the cell surface after 1 h ([Figure S6](#app1-materials-12-02567){ref-type="app"}). However, 2 h following treatment with BIM~A,cath,K~PA~2~, FITC-BIM~A~ was located more diffusely throughout the cells ([Figure 5](#materials-12-02567-f005){ref-type="fig"}), as was previously measured in identically treated HeLa cells ([Figure 2](#materials-12-02567-f002){ref-type="fig"}). Interestingly, the nuclei of these cells appeared fragmented, and bright field imaging revealed anoikic, rounded cells with membrane blebbing, classical hallmarks of apoptosis ([Figure 5](#materials-12-02567-f005){ref-type="fig"}). Meanwhile, WT MEFs pre-incubated with CA-074Me showed diminished FITC-BIM~A~ association that was confined to puncta near the edges of the cell membrane and lacked signs of apoptosis ([Figure 5](#materials-12-02567-f005){ref-type="fig"}). These data suggest that the earlier diffuse intracellular accumulation of the FITC-BIM~A~ peptide after delivery by the cleavable DSPE-PEG tail depended to some degree on cathepsin cleavage of the linker.
3.6. Apoptotic Cell Death Induction {#sec3dot6-materials-12-02567}
-----------------------------------
Given there were early signs suggestive of apoptosis in MEFs treated with BIM~A,cath,K~PA~2~, we next determined if treatment with BIM~A,cath,K~PA~2~ induced dose- and time-dependent cell death in these same cells. BIM~A,cath,K~PA~2~ induced progressive dose- and time-dependent cell death and corresponding caspase-3/7 activation in WT MEFs ([Figure 6](#materials-12-02567-f006){ref-type="fig"}a). The non-cleavable BIM~A,K~PA~2~ induced a lesser degree of cell death by 72 h with corresponding caspase activation ([Figure 6](#materials-12-02567-f006){ref-type="fig"}b). The BIM~A,K~ peptide alone, however, which was unable to enter cells ([Figure 2](#materials-12-02567-f002){ref-type="fig"}a), did not induce measurable cell death or caspase-3/7 activation ([Figure 6](#materials-12-02567-f006){ref-type="fig"}c). An inert BIM BH3 peptide (BIM~B~-MRPEIWIAQELRRIGDFNAKKKKK) was used as a peptide control in these studies. Importantly, BIM~A,cath,K~PA~2~ was unable to induce caspase-3/7 activation in MEFs lacking the pro-apoptotic effector proteins BAK and BAX (BAX^-/-^BAK^-/-^ MEFs), indicating specific activation of the intrinsic pathway of apoptosis rather than non-specific mitochondrial outer membrane disruption by either the BIM~A~ peptide or the DSPE-PEG tail ([Figure 6](#materials-12-02567-f006){ref-type="fig"}d). BIM~A,cath,K~PA~2~ and, to a lesser extent, BIM~A,K~PA~2~ also induced corresponding PARP cleavage in WT MEFs, another hallmark of apoptotic cell death ([Figure 6](#materials-12-02567-f006){ref-type="fig"}e).
4. Discussion {#sec4-materials-12-02567}
=============
Intracellular PPIs remain a great challenge to therapeutically target and are often therefore described as "undruggable" \[[@B36-materials-12-02567]\]. There is a new resurgence in research exploring how to effectively drug these challenging interfaces through orthosteric inhibition. PPIs are particularly challenging to drug using small molecules as the contact interfaces between proteins are usually distributed along geographically large surface areas and consist of a complex topographical interplay of polar and hydrophobic interactions. However, there has been some success in this area using relatively large small molecules such as the first in class BCL-2 inhibitor venetoclax, which recently gained FDA approval for use in patients with a number of hematological malignancies \[[@B37-materials-12-02567]\]. Peptides, on the other hand, have long been used as research tools to mimic fragments of proteins and disrupt PPIs. However, an enormous obstacle to their therapeutic relevance is their lack of intracellular accessibility. One strategy that has been quite successful at facilitating peptides' cell uptake is hydrocarbon-stapling of naturally α-helical peptides, and multiple clinical trials are now underway using a stapled peptide that therapeutically reactivates WT p53 in cancerous cells \[[@B38-materials-12-02567],[@B39-materials-12-02567],[@B40-materials-12-02567]\]. Nanomaterials, such as PAs, are also being widely explored for building delivery vehicles to carry unmodified therapeutic peptides into cells while at the same time protecting them from extracellular degradation \[[@B14-materials-12-02567]\].
PAs have been used to build supramolecular nanomaterials for numerous biomedical applications including therapeutics, diagnostics, regenerative medicine, and vaccines \[[@B41-materials-12-02567]\]. Most of these applications involve cell-material interactions occurring at the cellular surface. However, our group and others have also found that unimer PAs can use their lipid tails to directly interact with the cell membrane and trigger cell uptake \[[@B11-materials-12-02567],[@B12-materials-12-02567],[@B13-materials-12-02567],[@B17-materials-12-02567]\]. We have since studied the mechanisms by which a number of lipid tails facilitate such cellular penetration \[[@B13-materials-12-02567]\]. We have also determined that following lipid-mediated trafficking into endosomes, removal of the tail prevents lipid-mediated ejection and recycling of the peptide-laden PA back out of the cell and facilitates intracellular accumulation of the therapeutic peptide \[[@B18-materials-12-02567]\]. The current study expands upon these works by using cleavable PAs to deliver the bioactive BIM BH3 death domain into cells to induce apoptosis. The BIM BH3 domain is well known to potently induce apoptosis by manipulating the BCL-2 family of proteins' PPIs through induced-fit binding of both pro- and anti-apoptotic proteins, but only when the cell membrane is chemically permeabilized \[[@B24-materials-12-02567],[@B25-materials-12-02567]\]. Additionally, although stapled peptides are able to enter the cells, their potency can be greatly enhanced through outer cell membrane permeabilization \[[@B42-materials-12-02567]\].
Two similar PAs were tested, one with a PEG spacer (BIM~A,K~PA~2~) and one without (BIM~A,K~PA~1~), both with dialkyl lipid tails, for their ability to carry a BIM BH3 peptide into cells without non-specific disruption of the cell membrane. Although the diC16 PA (BIM~A,K~PA~1~) lacking the PEG spacer readily delivered the BIM~A~ peptide into cells, it also caused non-specific membrane disruption, a problematic, often not tested, off-target cytotoxic effect. Inclusion of a hydrophilic PEG spacer with a DSPE-PEG tail (BIM~A,K~PA~2~), meanwhile, eliminated membrane disruption. However, this addition led to inefficient intracellular localization of the peptide as cargo was seen primarily on or near the cell membrane surface. It is unclear if this was from tempered membrane crossing or from rapid endosomal recycling as our group has measured in other PA systems \[[@B13-materials-12-02567],[@B18-materials-12-02567]\]. However, the incorporation of the endosomally-cleavable valine-citrulline cathepsin-substrate linker into the DSPE-PEG PA (BIM~A,cath,K~PA~2~) amplified the peptide's intracellular accumulation, while still avoiding non-specific membrane disruption. It is likely the cathepsin linker allows for quick release of the BIM~A~ peptide and that the peptide was able to escape, to some extent, late endosomal/lysosomal trafficking and enter the cytoplasm. We have previously measured similar discrepancies in therapeutic peptide intracellular accumulation using a similar cleavage system between a peptide cargo and lipid tail carrier, indicating that the increased intracellular localization measured here is not a unique feature of the BIM~A~ peptide \[[@B41-materials-12-02567]\].
Removal of the lipid tail following cellular uptake proved to be important not only for intracellular trafficking and accumulation, but also for the peptide's ability to bind its target protein(s) and exert its therapeutic effect. As may be expected, addition of the DSPE-PEG tail inhibited the ability of the BIM BH3 peptide to bind to all antiapoptotic proteins tested (BCL-2, BCL-W, BCL-XL, and MCL-1). While BIM~A,K~PA~2~ and BIM~A,cath,K~PA~2~ were able to bind their target proteins, they did so with 2--3 fold lower affinity compared to the parent BIM~A,K~ peptide alone. It is important to note that the concentration of PAs used in the binding assays (50 nM) was well below their critical micellar concentrations (\>1 μM). Thereby, the differences in binding affinity were likely not due to supramolecular self-assembly, but rather due to steric hinderance within each unimer imparted by the DSPE-PEG tail. Cleavage of this tail, and the C-terminal lysines, greatly improved binding affinities of the BIM~A~ peptide to its target proteins, which translated to increased efficacy.
Finally, we measured the PAs' abilities to induce apoptosis after intracellular delivery. Both BIM~A,K~PA~2~ and BIM~A,cath,K~PA~2~ were able to enter cells and bind their target proteins, though the cathepsin-cleavable PA performed better at both cell uptake and target protein binding. It is possible that BIM~A,K~PA~2~ primarily resided in early/late endosomes near the cell surface and then rapidly recycled back to the cell membrane. While this may have also occurred to some extent with BIM~A,cath,K~PA~2~, some PA unimers may have been able to be cleaved upon transitioning to late endosomes upon acidification of these compartments and activation of cathepsin B. This transition and cleavage was largely blocked by cathepsin inhibition. As anticipated, the PAs' abilities to induce apoptosis correlated with these prerequisites. Both PAs were able to induce apoptosis, however, the cathepsin-cleavable PA did so with faster kinetics and at lower doses. Given that the peptides were not structurally reinforced (e.g., hydrocarbon stapled), it is unclear how much of the delivered peptide was able to escape the endosomal/lysosomal network. Studies evaluating the efficiency of intact delivery of native peptides into the cytoplasm of cells are currently underway and beyond the scope of the present study.
BIM~A,cath,K~PA~2~ was designed to release the peptide from the tail in the endosome, but this study did not intentionally include any mechanisms to facilitate endosomal escape. By an unknown mechanism, the released peptide was able to escape the endosome, reach the mitochondria, and activate apoptosis. In addition to cellular uptake, endosomal escape of nanoparticles and biofunctional warheads is another monumental obstacle to intracellular delivery of biologic therapeutics \[[@B23-materials-12-02567]\]. More work is needed to understand how otherwise cell-impermeable peptides are able to escape the endosome following internalization. The overall secondary structure and charge of the peptide is likely to be critical to organelle escape once internalized into the cell \[[@B10-materials-12-02567],[@B43-materials-12-02567]\].
This study expands on our explorations of how PA nanoparticles interact with cells and facilitate a therapeutic peptide's intracellular uptake and dissemination. While a lipid tail can improve a peptide's cellular uptake, our work supports the importance of removing the tail after uptake, not only to prevent recycling back out of the cell, but to prevent the tail from inhibiting the peptide's binding to its target and thereby dampening its therapeutic efficacy. Endosomal entrapment and lack of cytoplasmic access, as well as stability in circulation (i.e., binding to serum proteins) remain formidable and poorly understood obstacles in the clinical translation of lipid-based carrier nanoparticles \[[@B14-materials-12-02567],[@B41-materials-12-02567]\]. This study demonstrates, as proof-of-concept, that cathepsin-cleavable PAs can be used to deliver therapeutic peptides into cells to exert a biomedical effect. More research is warranted to understand the mechanisms behind membrane trafficking and endosomal escape in order to fully unlock the therapeutic potential of such peptide-based protein mimetics.
We would like to acknowledge the University of Chicago's Advanced Electron Microscopy Core Facility where the TEM images were acquired. Confocal microscopy images were acquired at the Universtiy of Chicago's Integrated Light Microscopy Core Facility, funded by the Cancer Center Support Grant P30CA014599. We would also like to thank the University of Chicago's Mass Spectrometry Core Facility, where the MALDI-TOF spectra were acquired, with support from the National Science Foundation (NSF) instrumentation grant CHE-1048528.
######
Click here for additional data file.
The following are available online at <https://www.mdpi.com/1996-1944/12/16/2567/s1>, Figure S1: MALDI-TOF spectrum of BIM~A,K~PA~1~. Expected molecular weight is 4001 Da; Figure S2: MALDI-TOF spectrum of BIM~A,cath,K~PA~2~. The expected average molecular weight is \~6452 Da, with polydispersity due to the PEG spacer in the tail; Figure S3: Live cell confocal microscopy of HeLa cells treated with FITC-labeled BIM~A,K~ peptide~,~ BIM~A,K~PA~2~, or BIM~A,cath,K~PA~2~ for 2 h followed by washing. Only BIM~A,cath,K~PA~2~ enabled FITC-peptide co-localization with MitoTracker-labeled mitochondria. Original magnification, ×100; Figure S4: Time-lapse, live cell confocal microscopy of HeLa cells treated with FITC-labeled BIM~A,cath,K~PA~2~. Cells were treated with 10 μM FITC-BIM~A,cath,K~PA~2~ for 2 h before being washed, stained, and imaged. FITC signal was first visible near the edges of the cell, and over 8 h, became diffusely fluorescent and co-localized with MitoTracker-labeled mitochondria. Original magnification, ×100; Figure S5: The cathepsin B inhibitor CA-074Me efficiently inhibits recombinant cathepsin B activity in vitro. Recombinant cathepsin B was added to a linker substrate that becomes fluorescent following cathepsin cleavage. The reaction was co-incubated with either CA-074Me or DMSO vehicle control; Figure S6: The cathepsin inhibitor, CA-074Me, inhibits BIM~A,cath,K~PA~2~'s cellular uptake. MEFs were pre-incubated with either 5 μM CA-074Me or 0.1% (*v*/*v*) DMSO control in complete media for 1 h. They were then washed and treated with 10 μM FITC-BIM~A,cath,K~PA~2~ for 1 h before washing, fixation, staining with Hoechst, and confocal imaging.
Conceptualization and methodology, J.L.L., M.V.T. and J.A.B.; investigation and formal analysis, J.A.B., R.S. and H.A.; writing---original draft preparation, M.R.S. and J.L.L.; writing---review and editing, M.R.S., M.V.T. and J.L.L.; supervision and funding acquisition, J.L.L., M.V.T.
M.S. was supported by the National Institutes of Health (NIH) as an F30 fellow (F30CA221250) and by the University of Chicago MSTP training grant (T32GM007281). This work was also supported by a Hoogland Lymphoma Research Award (J.L.).
The authors declare no conflict of interest.
{#materials-12-02567-f001}
{#materials-12-02567-f002}
{#materials-12-02567-f003}
{#materials-12-02567-f004}
{#materials-12-02567-f005}
{#materials-12-02567-f006}
[^1]: These authors contributed equally to this work.
[^2]: Current address: Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73071, USA.
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Q:
make an image go to the same speed of the finger in a scrollview
so I have a scrollView and an image inside? My problem is that when I scroll down the scroll view my image doesn't go to the same speed of my finger. What I would like is that this image goes to the same speed of my finger, thus my finger center is the image center . How can I do this please, sorry for my english I'm french /
A:
You want to setup a delegate for the UIScrollView and update the image position in this method:
-(void)scrollViewDidScroll:(UIScrollView*)scrollView;
{
CGPoint offset = scrollView.contentOffset;
// Now use offset to update the image's position.
// Be fast this method is called OFTEN!
}
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Anaplasma phagocytophilum seroprevalence in equids: a survey in Sicily (Italy).
This study was undertaken to determine the prevalence of Anaplasma phagocytophilum infection in Equidae and investigate the possibility of exposure to the organism in Sicily (Southern Italy). During the study blood samples were collected in horses and donkeys housed in five of the nine provinces of Sicilian Island. Of 133 horses and 100 donkeys tested, respectively 9.0% and 6.0% were seroactive (IFAT) with A. phagocytophilum antigen. In only 4.7% of the horses, specific A. phagocytophilum DNA was recorded; in donkey, Anaplasma DNA was not found. Our results indicate a low prevalence of A. phagocytophilum in Sicilian equids. This condition does not justify the exclusion of equids from prophylactic plans for this multihost pathogen infection, a zoonosis with a wide distribution in other European countries. However, further studies are necessary to elucidate the possible mechanisms that involve the Equidae as host of this pathogen. |
Introduction {#S0001}
============
Chief Residents (CRs) are typically chosen based on their clinical work as residents or as a set role during the final year of residency. Described as early as the 19th century, chief residents refer to senior residents that have demonstrated competence to manage and care for patients with minimal supervision \[[@CIT0001]\]. This role has evolved over the past century and the responsibilities of CRs vary among specialties, but what has remained constant is that CRs all are required to lead and mentor a diverse and often large group of residents. CRs tend to be responsible for multiple administrative, educational, and clinical components throughout the year. CRs oversee resident scheduling, compliance of programs with credentialing councils, as well as being supervisors of resident education \[[@CIT0001]\]. In addition to these administrative responsibilities, CRs learn how to be leaders by acting as a liaison between junior residents and clinical program leadership, resolving resident and interdisciplinary conflicts, and navigating the healthcare environment and health systems that involve senior directors and administrators. Effective clinician leadership has been shown to improve patient care by encouraging teamwork, promoting a culture that supports safe practices, and enabling innovation and continuous development of skills to promote better outcomes for patients and health-care systems \[[@CIT0002]\]. Being an effective leader is vital for success as a CR, though, CRs are not often chosen based on their ability to lead. In medical school and the early years of internship and residency, individuals focus on their clinical growth and expertise and have minimal exposure to leadership skills development \[[@CIT0001],[@CIT0003]\]. One such explanation for a lack of formal leadership training is that the 'creativity, innovation, and strategic insight required for successful leadership and management' are often seen as being at odds with the analytical skills that are the focus of medical education \[[@CIT0003]\]. Despite this lack of training, CRs are expected to demonstrate specific leadership skills to meet the demands of their newly acquired and influential roles.
Gewertz and Logan state that the challenge facing physicians, including CRs, who 'aspire to outstanding leadership is to continue to 'own' what makes them star performers as individuals, while shifting their focus to others' \[[@CIT0004]\]. As CRs transition into their new leadership roles, they must display a dual set of knowledge and expertise; an understanding of clinical medicine and additional proficiency in traditional business content \[[@CIT0003]\]. CRs, while maintaining a clinical leadership presence, must also transition to a new set of rules; focusing more on how their team's work gets done and less on the results themselves \[[@CIT0004]\]. This is not to say that clinical results no longer matter, but in leadership, there is a recognition that 'how results are achieved matters as much, and often much more.' \[[@CIT0004]\]
One of the skills found to be central to leadership, and can therefore ensure a smooth transition, is Emotional Intelligence (EI). EI is a relatively recent concept to be embraced within the organizational sphere; however, its definition can be dated back to the early 1900s \[[@CIT0005]\]. EI is associated with leadership success and encompasses four competencies: self-awareness, self-management, social awareness, and relationship management \[[@CIT0005]\]. The four-component model includes two distinct but interconnected domains; personal competence and social competence. To enact correctly, these four elements require the coordination of both the rational (thinking) mind and the emotional (feeling) mind. Daniel Goleman posits that while these two minds are well coordinated the majority of time and 'feelings are essential to thought, \[and\] thought to feeling', he recognizes that when the balance tips, it is often the emotional mind that captures the upper hand \[[@CIT0005]\]. Through EI teaching, an individual learns to first recognize his or her emotional response to a situation and to then manage this emotional response internally in an effort to improve his or her efficiency with decision making skills and positively influence outcomes \[[@CIT0002]\]. Substantial evidence in multiple professional fields shows that EI measures abilities critical for leaders and correlates with high performance. At the very highest levels, competence models for leadership typically range from 80 to 100 percent EI-related abilities \[[@CIT0005]\]. Many medical communities are acknowledging the value of EI skills for physician development as it promotes patient safety and satisfaction in addition to improving inter-professional cooperation \[[@CIT0006],[@CIT0007]\]. EI has been suggested for physician trainees for teaching interpersonal skills, communication, and professionalism, all of which contribute to the core competencies of the Accreditation Council for Graduate Medical Education (ACGME) \[[@CIT0008]\]. Various studies have also shown that medical professionals want EI training, yet there is a gap between the recognition of the need for EI training and the development of EI curricula in graduate medical education programs, with very little research focused on how EI can best be learned and assessed \[[@CIT0002],[@CIT0004],[@CIT0009]\]. Furthermore, there is no known average or accepted emotional intelligence score among resident physicians and that any EI intervention must be tailored to an individual resident or particular resident group \[[@CIT0010]\]. Leadership training courses have been implemented in various graduate medical education programs and some have focused on CR development through lecture series or formal mentorship programs \[[@CIT0006],[@CIT0011]--[@CIT0013]\]. Analysis of the benefit of these programs is based on post-program self-assessment surveys filled out by participants, but there does not seem to be a standard or optimal format for these programs that provides the most benefit.
The use of standardized learners in Objective Structured Teaching Encounters (OSTEs) has proven to be effective in assessing teaching skills of medical school faculty, residents, and medical students \[[@CIT0014]--[@CIT0016]\]. OSTEs are a pedagogy that support active application of learning after the delivery of content and function to assure actual learning is occurring. OSTEs also provide the framework to evaluate specific teaching competences with direct feedback given at the end of each encounter \[[@CIT0015]--[@CIT0018]\]. Most leadership development programs for physicians minimally use interactive learning and feedback \[[@CIT0016],[@CIT0017]\]. OSTEs, though, have been utilized to provide faculty development and feedback performance within the realm of undergraduate and graduate medical education \[[@CIT0014],[@CIT0015]\]. Given that OSTEs have been successful in these areas, it is reasonable to consider their use for leadership development and training. We believe that through this type of learning-in-action, with attention paid to emotional intelligence that new leadership and feedback skills can be expediently practiced to assure CRs are better prepared for their responsibilities as educational leaders.
Our program began with each participant completing an EI Inventory three weeks prior to the day-long program. The daylong experience begins with a series of didactic sessions that have a focus on leadership, managing, and core feedback skills. During this portion of the course, participants received their individual EI report, interpretation of their scores, and strategies to improve them. The third part of the program, which takes place during the second half of the day, reinforces the application of new knowledge through a four station OSTE skill building experience ([Figure 1](#F0001){ref-type="fig"}). This highly experiential portion of the course focuses on leadership and mentoring specific to interpersonal and communication skills and professionalism, core competencies required by the ACGME accreditation system and all requiring the underpinnings of EI.Figure 1.Sample OSTE content.
Methods {#S0002}
=======
Northwell Health is a large integrated health care organization consisting of 21 hospitals and over 450 ambulatory and research sites. Northwell Health is the institutional sponsor of 120 accredited and non-accredited GME training programs, with approximately 1600 residents and 100 chief residents annually. Incoming CRs from multiple GME programs (N = 100, 15 disciplines) were recruited to participate in one of four one-day, nine-hour courses prior to the start of their CR year. Participant recruitment was achieved through advertising sent to program directors, coordinators, and current chief residents. We had a goal of 20--25 participants at each of the four sessions.
Participants completed an online version of the TalentSmart® EI inventory assessment, that was available through our health system, approximately three weeks prior to the course. Theinventory follows the revised Goleman model of emotional intelligence \[[@CIT0005]\], which evaluates four separate components: self-awareness, self-management, social awareness and relationship management. The 'consultant education' version of this assessment was used and participants did not learn their scores until they attended the course. This prevented participants from focusing on the numbered result without first understanding the context of the score and the practical application to their future roles requiring new skills. On the day of the course, the results of the EI inventory were confidentially reviewed with each participant to clarify what the scores meant in order to identify existing strengths and areas for improvement. The intent was this new knowledge would be applied in the formative OSTE stations.
Senior training program educators (Program Directors, Leaders of Faculty Development and Physician Leadership Institute) lead sessions emphasizing leadership responsibilities applicable to the role of a CR, with a focus on skills necessary to deliver difficult feedback and strategies to assist with interpersonal conflict resolution among resident teams. The didactic session ended with a panel of current CRs joining the group to share their year-long experiences, thoughts on lessons learned as a CR, and best practices in leadership, managing, and mentoring.
The CRs were then divided into pairs to participate in OSTEs based on de-identified authentic incidents reported by previous CRs and collected anonymously using an electronic survey. In an effort to allow for more honest critique and feedback, the pairs purposely came from two different residency programs and individuals most often did not know their partners. The OSTE component occurred in a clinical skills center consisting of fourteen separate clinical encounter rooms. The standardized case script simulated clinical education situations in which the CRs needed to rely on EI to interact with and provide collaborative feedback to junior residents who presented difficult interpersonal and professionalism situations. Script content specifically addressed professionalism, confidentiality, issues of escalation, and teamwork ([Figure 1](#F0001){ref-type="fig"}). Actors in a standard format were educated to play the role of junior residents struggling with the several different scripted difficult situations. The CR pairs had two roles in the OSTE. One was to assume the role of the CR providing feedback and use EI skills with a junior resident presenting a difficult situation. The other role was to be a peer resident giving feedback to the CR learner. This was possible as the peer could observe and listen to the CR-resident interaction outside the encounter room. As there are four cases, each resident assumes each role twice. Feedback was organized via a checklist developed specifically to account for the skills addressed in the didactic sessions preceding the OSTEs. The CR, standardized resident, and peer observer each completed similar checklists prior to providing in person feedback ([Figure 2](#F0002){ref-type="fig"}). The encounter concluded with three-way feedback between the CR, standardized resident learner (actor), and peer resident observer who collectively reviewed the checklist to guide principles of collaborative coaching. The CRs debriefed as a group with their peers and a senior faculty member regarding communication, and professionalism behaviors, after the first two cases and then again after the last two cases. Debrief discussions focused on the content of the four OSTEs and making difficult decisions, maintaining confidentiality, and when to escalate issues or concerns to residency leadership. The debrief faculty completed a post session survey to document core issues addressed in the debrief session. A program agenda for the day is in [Figure 3](#F0003){ref-type="fig"}.Figure 2.Sample feedback check list (self-assessment). Figure 3.Outline of workshop.
Results {#S0003}
=======
The program had 20 chief residents each day, to total 80 residents across 15 clinical disciplines and included all health system hospitals that had GME training programs.
The aggregated mean pre-session EI score for all participants was 76.9. The EI score can range from 0--100, and research has shown that strong leaders have a mean EI score of 85 or higher; less than a score of 50 is considered very undesirable \[[@CIT0005]\]. The goal for our CR learners would be to move from their baseline score over time and progress to a higher score (85--100) as they continue their professional development as a physician.
An independent-samples t-test was conducted to compare the CRs' leadership and feedback performance as assessed by the CR, standardized learner and observer on the first and second OSTE performance. Performances were scored on a scale with a range of 0 to 100. There was a significant difference between the first OSTE performance (M = 47.92, SD = 7.8) and the second OSTE performance (M = 51.22, SD = 6.9); t (68) = 1.99, p = 0.006 ([Figure 4](#F0004){ref-type="fig"}). These results suggest that participating in multiple OSTEs that were specific to feedback and mentoring junior residents positively reinforces the core interpersonal and communication skills discussed in the didactic portion and practiced in the interactive portions of the program.Figure 4.OSTE performance.
The data gathered from post-program evaluation suggests the program achieved success at three different levels of Kirkpatrick's evaluation schema \[[@CIT0008]\]. Participants had a positive reaction to the experience (level 1) and learned critical leadership skills (level 2) that will help them be successful in the role of CR. Seventy-two percent of the residents stated they would recommend a similar experience to colleagues, 87% stated the program was useful, and 92% agreed that the program met their learning needs, while 90% of the residents agreed or strongly agreed that the objectives were met. In addition, the post-program evaluation suggests that the skills learned will lead to behavior change and overall organization impact (level 3). Seventy-six percent felt the course would help them to be more effective at work. CRs also reported positive comments about their OSTE experience: 'I enjoyed and felt the OSTEs were valuable for self-discovery;' 'The simulations were good and so was the feedback after the OSTE (by standardized learner);' 'Good scenarios, the practice will aid me in teaching junior residents;' 'The OSTEs were true to life.' Themes identified in the feedback from CRs included the observation that self-assessment is helpful in increasing self-awareness and the opportunity to practice mentoring residents and apply the S-FED (Self Assessment; Feedback; Encouragement; Direction) coaching model is instrumental in the development of communication and feedback competencies \[[@CIT0005]\]. Feedback was also gathered from the senior faculty who debriefed the OSTE experience with CRs. When asked about their impression of the effectiveness of the session, a representative faculty statement was that it was 'an excellent session in which I got the impression that most of the incoming chiefs felt they benefited'.
Conclusion {#S0004}
==========
This communication showcases the efforts of one large academic healthcare organization with a large number of residencies and fellowships to centralize education programs for CRs. Our goal was to help CRs start their new role with appropriate education and be well prepared for challenges they are likely to encounter within their respective training programs, as well as perform at the level expected by their Program Directors and organizational GME leadership. Our primary focus on EI principles as a core competency is based on an extensive literature on leadership, which by extension supports EI as a tool for GME training initiatives. The pre-intervention EI scores of our participants reported are below the mean score that is expected for strong leaders \[[@CIT0005]\]. This reinforced the need for participation in structured education, which included didactic content and, more importantly, provided an opportunity to practice skills and apply the EI principles in a favorable learning environment.
OSTEs designed specifically for CR physicians hold great promise for rapid and rigorous formative assessment of clinical teaching skills and support experiential curricular efforts. In addition they simulate the clinical environment where leadership and mentorship skills can be applied with individual residents and allow for standardized teaching and assessment \[[@CIT0018],[@CIT0019]\]. As seen with prior studies, our study shows that OSTEs along with post-OSTE debriefing sessions can provide a platform by which learners (particularly CRs) can demonstrate competencies in areas that are often ignored, missed, or even considered 'hidden' \[[@CIT0015],[@CIT0016]\]. CR education in these areas is essential as CRs are increasingly recognized as critically important teachers for their peers and medical students.
As with any educational intervention we encountered limitations. We acknowledge our study is limited to CRs within one health system, with the caveat that we have 100 chief residents across 21 hospitals in all disciplines of medicine with about 80 individual participants. Their exposure to EI training is minimal and that could be much more extensive, but the logistics of GME make this difficult earlier in their training. EI is best learned over time through consistent attention and feedback on EI principles and future follow-up sessions ('come-back' sessions) would reinforce skills introduced prior to beginning their CR role. Our post-OSTE debriefs were relatively unstructured; in the future we could develop a more structured format that could add to CR learning and self-reflection \[[@CIT0015]\]. If resources allowed, we would also like our OSTE exposure to be more of a summative assessment. This could include expanding to eight total stations and allowing for a greater degree of feedback for participants. As well, we would consider inclusion of EI training for our standardized learners and faculty observers in order to provide additional collaborative feedback. We could also consider comparing the evaluations made by our CRs to the standardized learners and observers to account for the often poor self-assessment individuals tend to provide.
Our results do suggest that CRs, across multiple disciplines, who participated in a one-day combined didactic and experiential educational program can practice communication and professionalism behaviors that support core leadership and feedback skills. Optimizing these abilities are critical for success in their upcoming administrative and leadership roles. Most importantly the acquisition of this knowledge and skills can help assure the role of CR is a positive experience that may influence future career choices at academic health systems that include clinical, academic, and administrative roles. Towards this, we encouraged all CRs to return for optional 'CR comeback' educational sessions during their CR year. These sessions are focused on advanced learning topics and also include experiential simulation experiences. An opportunity to re-take the EI inventory prior to completion of their CR year, for additional self-awareness is also offered to all participants. An additional EI score six-months post-residency can provide further assessment of a sustained effect of this experiential program during the chief resident year.
Note {#S0005}
====
This manuscript has not been published elsewhere and has not been submitted simultaneously for publication elsewhere. All authors have read and approved the final manuscript.
A special thank you to Wendy Herman, Education and Liaison Librarian of Hofstra University for her help with our literature search.
Disclosure statement {#S0006}
====================
Andrew Yacht, MD provides consultancy services and ad hoc case reviews for NY State Office of Professional Medical Conduct. No other potential conflicts of interest were reported by the authors
|
Anglo-Russian
For the military-historical term see Anglo-Russian invasion of Holland, Anglo-Russian invasion of Naples, for the political term see Anglo-Russian Entente
The Anglo-Russians were an English expatriate business community centred in St Petersburg, then also Moscow, from the 1730s till the 1920s. This community was established against the background of Peter I's recruitment of foreign engineers for his new capital, and generally cooperative diplomatic relations between the Russian and British empires. Some of the families were resident in Russia for several generations, though generally retaining UK citizenship and sending their children to be educated in England. Some lived there for so long that their English acquired a distinctive accent peculiar to Anglo-Russians.
Notable Anglo-Russian families were built around the trading houses and businesses of the Cazalet family, - the Cazalet-Miller business empire including the Ebsworth family, and Whishaw family. One of the first Anglo-Russian families was established by Noah Cazalet (1757-1800), a silk weaver, settled in St Petersburg and expanded into the burgeoning business of rope manufacture for sailing ships. In 1860 Edward Cazalet married an Elizabeth Marshall, and became connected to the company of William Miller & Co, of Leith in Scotland. The Whishaw family, of Hills and Whishaw Ltd, included James Whishaw, and influential intermediary in development of the Baku oilfields and Stella Zoe Whishaw, later Baroness Meyendorff, an Anglo-Russian actress who wrote a memoir Through terror to freedom - the dramatic story of an Englishwoman's life and adventures in Russia before, during & after the revolution in 1929, and then became a film diva in the 1930s.
A fictional account of Anglo-Russians is found in Penelope Fitzgerald's The Beginning of Spring (London, 1988).
Russian people of English descent
Nothing is recorded of the children of Joseph Billings (c.1758-1806) an English navigator who joined the Tsar's navy and settled in Russia. More notable are the descendants of William Sherwood, an English cotton machine engineer who came to Russia in 1800. (1798 at the invitation of Tsar Paul I according to family papers (Marcus Sherwood-Jenkins). His sons were John Sherwood, (Ivan Shervud in Russian) an influential lieutenant to Alexander I and Joseph Sherwood, who died in 1832 when his son Vladimir Osipovich Sherwood, later a famous architect (responsible for the building of The State Historical Museum on Red Square, Moscow.), was five years old. William's descendants include great-grandsons Vladimir Vladimirovich Sherwood, also an architect, and Leonid Sherwood, a sculptor, and great-great-grandson, the artist Vladimir Favorsky.
John Sherwood (Ivan Shervud) was responsible for unmasking the Decemberist plot in 1825 and was ennobled by the Tsar for his services and given the honorific Shervud Vernyi (Sherwood the loyal).
In addition there were the expatriate-born children of British businessmen in Russia, such as conductor Albert Coates, whose father was general manager for a British company in St Petersburg. He was raised from the age of 12 in England. Chess playing sisters Vera Menchik and Olga Menchik were daughters of a Czech father and English mother in Moscow, who moved to Britain in 1921 when the sisters were 15 and 13 years old.
See also
Russians in the United Kingdom
References
Category:English diaspora
Category:Saint Petersburg |
[Thoracoscopically assisted en bloc esophagectomy].
We report outcomes of en bloc esophageal resection with a thoracoscopically assisted laparotomy approach. The operation data were as follows: 41 thoracoscopically assisted procedures, 41 intrathoracic anastomoses, conversion rate 0, 100% R0 resection rate, 25 (15-52) lymph node retrievals, leak rate 2, and one mortality. From these results we conclude that minimally invasive esophagectomy with high intrathoracic anastomosis is a safe procedure. The R0 resection rate, lymph node retrieval, and operating time are comparable with those of the open abdominothoracic approach. |
The present invention relates to small animal control devices, in particular a convertible leash for guard dogs.
There have been various means to control small animals and pets by the use of a hand-held leash. Leashes have been devised in various configurations, either as a single strap attached to a collar around the animals neck or attached by a harness which encircles the animal""s body to prevent escape and relieve the focus of control pressure from the animal""s neck and to completely control the position of the animal""s body and the forces applied to it. A halter-type control device is similar but has a cinch characteristic in which the greater the control pressure applied to the leash the greater the level of discomfort is inflicted to discourage the animal from pulling against the control.
Dogs trained for guard, security, riot or crowd control or search and rescue cannot have their temperament or concentration altered or aggressiveness limited by an leash or harness that would tend to restrict or retard their highly trained attitudes in stressful or tense situations. Narcotics search requires a team effort between dog and handler in all types of environments and the dog must be protected, yet a freedom of motion and agility must not be hindered in any manner. Dogs used for guard duty are selected from rather large animals that can be trained to work with the handler and take commands while possessing a demeanor to frighten and control a suspect. Security and crowd control dogs posses the ability to be threatening and move crowds of people as quickly as possible without injury to people or the animal. These dogs are trained to attack if necessary. The handlers leash or tether is the only attachment used to control the dog. Noise and confusion usually requires greater strength of the handler and the ruggedness and reliability of the leash. One handed control may be necessary. Search and rescue dogs must have the unhampered opportunity to concentrate and detect or smell very small quantity""s of odor. Many of these situations can be in locations that are potentially dangerous to the dog, such as steep banks, pits, crevasses or the fast running water of streams and rivers. A dog can swim more efficiently if the front and rear legs are unhampered by a cumbersome harness. A loosely fitted body strap attached to the collar offers a safe and secure alternative to the harness while allowing complete swimming motion to the dog.
Thus, in the case of watch dogs, guard dogs and search dogs there is a specific need for a leash-type dog control in which the movement of the dog may be controlled without pain or discomfort applied to the body of the dog as the forward force increases, as in the case of a halter-type leash. Thus, a leash with a harness is preferred for police or military guard dogs, however, these can be bulky and difficult to apply as well as requiring different sizes to fit the size of the dog. If an attempt is made to simplify the harness by using a collar only, the collar may be slipped from the dog""s head and control of the dog is lost. Furthermore, there are varying conditions where a harness may be desirable or a simple collar may be desired, however, no prior art device is known which is easily convertible between the two control configurations.
Adequate control of a dog is not only needed in cases of guard dogs or police dogs, but also high-spirited domestic pet dogs can become hyperactive and need more control than a standard collar can provide. Many dogs, in extremely tense situations have developed the ability to slip their collar, and once loose, can subject themselves to uncontrolled danger. The only method of controlling dogs of this type is a choke collar or a harness. The choker chain used by an inexperienced handler can cause injury to the dog. Dogs of very calm temperament can become extremely excited due to situations such as traffic, other dogs, a sudden loud noise, etc. with tragic results. Heretofore a tight-fitting collar has been the only solution, however, it is most uncomfortable for the dog and can cause injury during sudden bursts of abnormal behavior. On the other hand, a normally loose-fitting collar that provides comfort for the dog is an invitation for problems as in the tense situations described above. In these situations a harness is preferred.
The closest patent prior art of which the Applicant is aware is U.S. Pat. No. 5,682,840 issued to McFarland on Nov. 4, 1997. This reference discloses a halter-type harness with cinching loops that encircle each of the dog""s front legs which apply discomfort to the dog the harder it pulls on the leash. The loops are formed by cords which pass through a slip ring which is tethered to the collar a short distance along the dog""s back to a point between its shoulders. A second ring is located at the end of the cinch cords for attachment of a conventional single strand leash. The device shown in this reference is just another means for creating for a halter control which has the disadvantages mentioned above and cannot be used as a control leash.
There is therefore a need in the art for a convenient, effective and economical control leash for guard dogs and search dogs which provides the advantages of a harness-type control configuration without its complexity.
In order to solve the problems in the art described above, the present invention has been devised which is simple, economical and easily convertible between a simple collar control leash or a harness. The device is a single strand leash which has a large, intermediate cinch-ring located a short distance along the leash from the point at which the leash fastens to the dog""s collar. As will be further described herein, by encircling the dog""s body and applying the well-known saddle-hitch-type knot to the free end length of the leash utilizing the cinch-ring, a harness-type control may be quickly and easily created. Furthermore, the knot may be tied while the collar and leash are on the dog so that a correctly sized harness strap looped behind the dog""s mid-section can be created. After tying-off the body loop, the free end of the leash grasped by the handler simply trails from the end of the knot behind the cinch-ring. Because the saddle-hitch-type knot is non-cinching, a harness rather than halter-top-type control is provided with the desirable characteristics as described above.
As an alternate embodiment of the present invention, an adjustable short strap with clip hooks at either end may be added as an optional way of forming the body-encircling loop. This additional length of strapping may also be clipped at both ends to a terminating loop at the end of the main leash to form a convenient loop handle when not employed as the body-encircling loop.
Therefore, the present invention has overcome the various problems of the prior art described above. It is thus the main object of the present invention to provide a harness and leash configurable from a simple, single strand element. It is further the object of the present invention to provide a leash which is convertible between a harness and simple collar configuration. An even further object of the present invention is to provide a simple, economical leash which is configurable into a harness-type control that may easily be adjusted to fit dogs of different size. These and other objects of the present invention will be apparent to those of skill in the art from the following description of the preferred embodiment. |
Pages
Sunday, October 21, 2012
The China Brief, a publication of the Jamestown Foundation in Washington, published an article titled "A New Egypt Looks to China for Balance and Leverage" by Chris Zambelis on 21 September 2012.
The article points out that Egyptian President Muhammed Morsi made his first visit (28-30 August) outside the Middle East to China and not the United States. Zambelis argued that Morsi and his Freedom and Justice Party want to diversify Egypt's foreign relations away from former President Mubarak's strong orientation toward the United States. Morsi's trip was also designed to reassure Beijing of post-revolutionary Egypt's intent to preserve its long-standing bilateral relationship with China. |
Specifications
Description
Delicate silver chain necklace set with a cz flower in centre. Matching earrings to complete the look. Silver finish. . A beautiful and affordable gift for your loved one. Our jewellery is nickel free, lead free and non-allergic to all skin types silver castle provides certificate of purity of silver with this product. .get free fashion bangle with this purchase.
Terms & Conditions
The images represent actual product though color of the image and product may slightly differ. |
Who doesn’t love the juicy, tropical smell of mango? I’m not that wild about fruity fragrances but I do like mango blends. They are like a little vacation in a bottle. Mango is sweet, pulpy, and peach-like a.k.a. delicious. Actually, I prefer this aroma in fragrance over a peach any day. Here is a list of fragrances heavy on mango in a variety of price points and mediums.
I love plums. We have a plum tree in the backyard and this spring brought us the most amazing aroma of plum blossoms. Plus, the tree has been just beautiful when covered with blossoms. It’s been quite a view from my pink boudoir. I also love the aroma of the juicy fruit. Stone fruits really add to a fragrance. A plum has a richness that others do not, plus it lacks the “fuzziness” of peaches. It mixes well with florals and spices. Hey, it even mixes well with seaweed. I would love a fragrance that smells like plum furikake. I’ve compiled a brief “collage” of various plum heavy fragrances. Feel free to add.
Budget Plum Scents (under $50):TokyoMilk Parfum Sugar Plum Solid Perfumeis a sweet plum as the name implies. It retails for $18. Bath and Body Works has 2 fruity plum floral EDTs: Cherry Blossom and Blushing Cherry Blossom. Both retail for $26.50 for over 2 ounces. An “oriental” plum is Avon Imari Seduction EDT. This is a “purple” seductive fragrance with vanilla, plum, and orchids. The 1.7 oz. goes for $22.50. Crazylibellule & The Poppies 26 Juin ile d’Yeu Solid Cologne is a refreshing plum/fruity chypre. The crazystick goes for about $18. To me it smells like a plum tree full of ripe fruit on a hot summer day. I really do love that stick. Aroma M Geisha Pink Roll-On is a frivolous sweet, sugared plum fragrance oil in an adorable package. It retails for $40.
More Expensive Plum Scents:Juicy Couture Couture Couture EDP is a very sweet fruity-floral with plum. It’s a bit too sweet for my taste, but it does have candied plums. The bottle is beautiful. The 1.7 ounce goes for $65. Creed Aqua Florentine is a light-hearted fruity floral with dessert plums, flirty blossoms, and cedar. The smallest spray retails for $130. Parfums des Beaux Arts by DSH Quincridone Violet EDP (not pictured) is an energetic plum/fruity violet floral. The 1 oz. EDP spray retails for $65. If a plum based fragrance could be an edgy fashionista, it would be Editions de Parfums Le Parfum de Therese. This is a blend of stone fruits, citrus, cedar, and leather. Love it. The 1.7 ounce retails for $155. If you are looking for a dried plum AKA prune fragrance, more appropriate for fall/winter, give Serge Lutens Bois et Fruits EDP a try. It’s woodsy and powdery sweet. It retails for $200 for 1.7 ounces.
Ylang-ylang is a note that I have learned to love. It’s tenacity always turned me off. I never felt like I could pull-off such a heady, floral note. As I’ve “matured” to put it nicely, I’ve realized that I can pull-off ylang-ylang. If you can pull-off jasmine than you can do ylang-ylang. It’s a special fragrance, very exotic for me since I’ve shunned it for so many years. Here is a very brief ylang-ylang fragrance guide with varying price points.
Budget Ylang-Ylang Scents:Lush Flower Market Perfume is an old-fashioned blend of ylang-ylang, carnation, and violets. I like the scent but I get so overwhelmed in Lush markets that I can’t pull this apart. So, I assume that I really like this natural blend. The 1.3 oz goes for about $40. Cacharel Anaïs Anaïs EDT is a floral blend with ylang-ylang, jasmine, rose, and lilies. It’s a nice scent that unfortunately now is seen as old-fashioned. The 1.7 oz. spray goes for under $50. Demeter PMU in Ylang Ylang is a pure, tropical, short-wearing soliflore. The 1 oz spray goes for $20. Demter PMUs also make nice linen/room sprays. Nuts Cream Perfume in Ylang Ylang d’Amore (not pictured) is a nourishing cream perfume that is heavy on this tropical, romantic floral in a moisturizing solid form. It goes for $12. Black Phoenix Alchemy Lab Ars Amatoria Suspiro is a intoxicating white floral blend with exotic white blossoms and dainty lilies. Black Phoenix Alchemy Lab Excolo Skuld is a sweet and sticky ylang-ylang with honey and resins. (Both are not pictured and retail for $15 for .5 oz oil).
Moe Expensive Ylang-Ylang Scents: Estee Lauder Private Collection Amber Ylang-Ylang EDP is a warm, rich, sexy ylang-ylang based scent. It’s a nice modern oriental. The 2.5 oz spray goes for $135. There is a pure parfum with a breathtaking bottle that costs much more and I haven’t had the opportunity to sample it. Tom Ford Private Blends Musk Pure EDP goes for $180 for 1.7 oz. Imagine a ylang-ylang, tonka, and musk and you have this. I like it for a floral musk scent. The ylang-ylang feels almost powdery against the musk. A more floral ylang-ylang based scent is Henry Dunay Sabi EDP. It has floral notes of ylang-ylang, rose, and jasmine. It retails for $110 for 1.7 oz.Annick Goutal Songes EDT is a tropical floral blend of ylang-ylang, frangipani, jasmine with a dry-down of vanilla. The 1.7 oz retails for $80.
Almond is a scent that I really enjoy in fragrance. I like the foody smell of toasted almonds and even that low-brow almond used in cheap Italian soaps and lotions. I find that almond is a very comforting scent and very versatile. Here is a guide to almond fragrances in a variety of price points.
Budget Almond Scents (Under $50 or $50):Villainess Silk & Cyanide Perfume Oil (not pictured) is a crisp almond scent. It retails for $18. Laura Mercier Eau Gourmande Almond Coconut is a sweet almondy floral with almond and coconut with flirty touches of heliotrope and jasmine. The 1.7 oz spray retails for $50. Carol’s Daughter Almond Cookie EDT is a marizapan like fragrance, very foody. The 2 oz. goes for $27. Provence Santé Almond EDT is a nice, innocent, and simple almond. It reminds me of nice Italian soap bars and wears nicely in the summer. It’s light wearing and the 3.4 oz bottle goes for under $30. I love it. Demeter PMU has Almond which is a lightly toasted almond fragrance. It’s nice and simple as well but doesn’t wear for very long. This cologne goes for $20 for 1 oz.
More Expensive Almond Scents: Aqua di Parma Mandorlo di Sicilia/Sicilian Almond EDT is a fresh but woodsy almond. It is one of my “preferred” almonds because of the cedarwood and its freshness. The 2 oz. spray retails for $68. Burberry Brit EDPdefinitely has a sugary, toasted almond dry-down. It has citrus and fruit notes. It is a sweet fragrance. The 1.7 oz goes for $68. Sarah Horowitz Comes From Within Joy EDP is a very wintery/Christmas-y foody, comforting almond scent with rich nutmeg and vanilla. The 1.7 oz retails for $95. Serge Lutens Louve EDP is a “white” almond scent that pairs nicely with its feminine florals of rose and jasmine; powdery and soft. The 1.7 retails for $140. Stephanie de Saint-Aignana Amamde Honorable EDT is a soft, tender almond blend with citrusy blossoms like linden. It retails for $135 for 1.7 oz. HanaeMori Butterfly EDP is a gourmand with berries, vanilla, and almond. The 1.7 oz retails for $90. Montale Amandes Orientales is a raw almond scent with vanilla, bitter but sweet. The 1.7 oz goes for $95.
I love the scent of honeysuckle. It’s such a nostalgic scent for me. What I have realized after I moved across the country, is that honeysuckle isn’t the same. It appears to vary from region to region. In our back yard here in the PNW, we have these orange honeysuckle blossoms. The blossoms smell jasmine-ish and sweet, but they are far less sweeter and honey-ish than the white ones that I grew up with in the South. I’ve tried to keep an open mind to the different honeysuckle based fragrances that I try. I try to keep in mind that there is more than one honeysuckle and many fragrance houses use the term loosely. Here is a list of honeysuckle based fragrances in a variety of price points. Every spring I get a honeysuckle “bug”. I’m sure I will this year too. Please share any that you like so that I can give them a try. One of my favorites was the now discontinued Cynthia Rowley EDP (not the Avon one). It was heavy on honeysuckle and many other flirty florals.
Bargain Honeysuckle Scents: Yves Rocher has Fraîcheur Vegetale Honeysuckle/Chevrefeuille Cologne, it is light-wearing but very pretty and refreshing. It retails for $20 (watch the website for mega-sales and BOGO). Melissa Flagg Clementine (my review)is one of my favorite scents with its blend of orange blossom and honeysuckle. It retails for $32. Now a solid is available. I haven’t tried it yet. Bath & Body Works Wild Honeysuckle EDT is much more floral than sweet and retails for $26.50. A single note honeysuckle is Demeter Honeysuckle which retails for $20. It is pretty and I only wish it would last longer! Mary Kay has an EDT, Sparkling Honeysuckle, that is sunny and fresh. It retails for $25.
More Expensive Honeysuckle Scents: A classic honeysuckle soliflore is Calypso Chevrefeuille EDT that retails for $55. An intoxicating honeysuckle scent is Jo Malone Honeysuckle & Jasmine Cologne. Jasmine and honeysuckle were meant to be together in a blend. The largest bottle retails for $100. A fresh and flirty honeysuckle oh, and a classic is Annick Goutal Le Chevrefeuille EDT. The largest size gos for $115. Creed Chevrefeuille is rugged and “pastoral” kind of honeysuckle, much more green than the others listed. I like it and it retails for about $150. It really does stand apart from the others listed.
Plus 5 More Nice Honeysuckle Blends:Miller Harris Fleur de Matin is a green, fresh scent with honeysuckle. I think of it as a nice summer honeysuckle. CieloNapa Valley (my review) is a blend that is heavier on fig and honey but the addition of honeysuckle type notes are very nice. It’s a sweet fragrance that I love for fall. Harajuku Lovers Music EDT is a sweeter honeysuckle scent with adorable packaging. I love the crisp “green” with honeysuckle in Annick Goutal Eau de Camille. It is so easy to wear and very flirty. Victoria’s Secret Dream Angel’s WishEDP is a very fruity floral with a kiss of honeysuckle. It isn’t my favorite in the list, but I feel I should list it.
I can’t wear cherry fragrances because my husband says that I smell like a urinal cake if I do. Since I spend no time in a men’s restroom, I can’t contest. I just have to take his word for it. Fortunately, you don’t just have to smell like a cherry jolly rancher when it comes to cherry. There are many cherry blends and cherry blossom fragrances on the market. I’ve made a list of cherry fruit and cherry blossom fragrances in many price points.
Bargain Cherry Scents (under $40):The Body Shop Japanese Cherry Blossom EDT is a green, fresh floral bouquet. The 1.7 oz spray retails for $25. Avon Fire Me Up EDT is a fruity blend of black cherry, citrus, and pomegranate. The 1.7 oz retails for $16. Melissa Flagg Sadie’s Perfume Roll-On is a romantic blend of cherry and plum blossoms floating on white tea. I think this is my favorite cherry blossom scent. The roll-on goes for $28. Bath and Body Works has a few cherry blossom scents but I’d say their most popular is Cherry Blossom EDT. It is a blend of juicy fruits and delicate flowers with cherry blossom. The 2.5 oz goes for $26.50. Demeter PMU in Cherry Blossom is a light-wearing cherry blossom scent. The 1 oz cologne goes for $20.
More Expensive Cherry Scents:L’Occitane Cherry Blossom EDT is a light, springy floral fragrance. It’s light, airy, and soft. The 3.4 oz retails for about $46. Cartier Délices de Cartier is a sweet, gourmand like fragrance. The top not is Morello cherry. It is then followed by jasmine, vanilla, and tonka bean. The 1.6 oz EDP goes for $100. Annick Goutal Quel Amour EDT is a bubbley, fruity, rose floral with Morello cherry. The 3.4 oz goes for $115.Ed Hardy Love & Luck is a sweet fruity fragrance with cherry blossom, sake, plum, and blood orange. The 1.7 oz goes for $55. Victoria’s Secret Sexy Little Things Ooh La La EDP is a fruity floral with citrus, cherry blossom, and sweet vanilla. I think the 3.4 oz goes for $49. Hilde Soliani Doolciiisssimo is an interesting guilty pleasure of mine. It is a blend of cherry tobacco, which I have always thought smelled great, with vanilla and patchouli. The 3.4 EDP goes for $175.
Mmmm, ginger. It has a great flavor and a great fragrance. This rhizome is spicy, warming, but still fresh, earthy, and a bit “green”. It is a note that works well in warmer climates and it is a note that does well in cooler weather. Now that the nights are getting cooler, I am more attracted to the “warmth” that ginger gives. Right now I am craving “spicy” ginger/gingerbread-ish scents. I know that in the middle of summer I’ll love some of those “green” ginger scents.
Bargain Ginger Scents: For some reason I think when other people think of ginger scents they automatically think of Origins Ginger Essence Skin Scent. It is a very nice scent and one of my favorite ginger scents on the market. It is refreshing with citrus and warming with ginger. It’s therapeutic. The 1.7 oz spray retails for $37. The price is nice too. A beach friendly ginger scent is Urban Rituelle Beachcomber Coconut & Ginger. The travel sized spray goes for $10. Apivita Spice Fragrance is what the name says, “spice” which is a blend of ginger, bergamot, caraway. The travel sized spray goes for $12. Demeter has three colognes worth mentioning: Gingerale (one of my favorite Demeter fragrances, smells like the real deal, fizzy and everything), Gingerbread (great winter comfort scent), Ginger Cookie (a sweeter version of gingerbread, also nice for winter), and Fresh Ginger (smells like the real thing). All of these come in a 1 oz for $20.
More Expensive Ginger Scents (over $50): Lush Ginger Perfume is a slightly fruity-floral ginger blend with classic florals and juniperberry. The 1.3 oz. spray goes for about $60. Yosh Ginger Ciao is an interesting ginger blend with black coconut, ylang-ylang, and neroli. It is like a tropical ginger scent, an island ginger. The perfume oil goes for $130. If you want a spicy ginger scent, try Jo Malone Nutmeg & Ginger Cologne. It’s warm, woody, and zesty. I like it for cooler weather. The 3.4 oz bottle retails for $100. A spicy, woodsy ginger blend is Van Cleef & Arpels Exclusive Cologne Noire EDP. It has cardomom (one of my weaknesses), bitter citrus, and woods. It retails for $185. It is more like gingerbread with hot tea and that is why I love this scent for winter: Serge Lutens Five O’Clock Au Gingembre. It’s a warming, comforting fragrance (that’s an understatement). The 1.7 oz bottle goes for $120. Cinq Modes Pluie d’Aromes Ritual de Kyoto, Japan is a ginger floral with ginger and rose. I do love a spicy rose scent. The 1.7 oz goes for $85. Montale Ginger Musk is a romantic ginger blend with berries and white musk. The 1.7 oz goes for $95. A nice summer ginger is Hilde Soliani Freschiiissimo. This is a fresh blend of lime, brown sugar, and ginger. Doesn’t that sound like it would make a great mixed drink? The 3.4 oz goes for $175. If you want a green, almost foresty, ginger try Vero Profumo Onda. It has vetiver, ginger, mace, and coriander. The perfume oil retails for $185. Parfums des Beaux Arts by DSH (neither pictured) has two ginger based scents. Gingembre (my review here) is a spicy, wintery, warming gourmand. The 1 oz. EDP goes for $70. The other is more of a summery, citrus ginger, Indochine. This one is loaded with citrus, basil, and white flowers. The 1 oz EDP goes for $65. |
Nattokinase is a potent fibrinolytic enzyme extracted and highly purified from a traditional Japanese food called Natto. Natto is a fermented cheese-like food that has been used in Japan for over 1000 years for its popular taste and as a folk remedy for heart and vascular diseases. Natto is produced by a fermentation process by adding Bacillus natto, a benefical bacteria, to boiled soybeans. The resulting nattokinase enzyme, is produced when Bacillus natto acts on the soybeans. While other soy foods contain enzymes, it is only the natto preparation that contains the specific nattokinase enzyme.
The Discovery of Nattokinase
Doctor Hiroyuki Sumi had long researched thrombolytic enzymes searching for a natural agent that could successfully dissolve thrombus associated with cardiac and cerebral infarction (blood clots associated with heart attacks and stroke). Sumi discovered nattokinase in 1980 while working as a researcher and majoring in physiological chemistry at Chicago University Medical School. After testing over 173 natural foods as potential thrombolytic agents, Sumi found what he was looking for when Natto was dropped onto artificial thrombus (fibrin) in a Petri dish and allowed it to stand at 37 C (approximately body temperature). The thrombus around the natto dissolved gradually and had completely dissolved within 18 hours. Sumi named the newly discovered enzyme "nattokinase", which means "enzyme in natto". Sumi commented that nattokinase showed "a potency matched by no other enzyme." 1,7
Potent Thrombolytic Activity
The human body produces several types of enzymes for making thrombus, but only one main enzyme for breaking it down and dissolving it - plasmin. The properties of nattokinase closely resemble plasmin. According to Dr. Martin Milner, from the Center for Natural Medicine in Portland, Oregon, what makes nattokinase a particularly potent treatment, is that it enhances the body's natural ability to fight blood clots in several different ways; Because it so closely resembles plasmin, it dissolves fibrin directly. In addition, it also enhances the body's production of both plasmin and other clot-dissolving agents, including urokinase (endogenous). "In some ways, Milner says, nattokinase is actually superior to conventional clot-dissolving drugs. T-PAs (tissue plasminogen activators) like urokinase (the drug), are only effective when taken intravenously and often fail simply because a stroke or heart attack victim's arteries have hardened beyond the point where they can be treated by any other clot-dissolving agent. Nattokinase, however, can help prevent that hardening with an oral dose of as little as 100 mg a day." 1,7
The Prolonged Action of Nattokinase
Nattokinase produces a prolonged action (unlike antithrombin drugs that wear off shortly after IV treatment is discontinued) in two ways: it prevents coagulation of blood and it dissolves existing thrombus. Both the efficacy and the prolonged action of NK can be determined by measuring levels of EFA (euglobulin fibrinolytic activity) and FDP (fibrin degradation products), which both become elevated as fibrin is being dissolved. By measuring EFA & FDP levels, activity of NK has been determined to last from 8 to 12 hours. An additional parameter for confirming the action of NK following oral administration is a rise in blood levels of TPA antigen (tissue plasminogen activator), which indicates a release of TPA from the endothelial cells and/or the liver.6,7
The Mechanism Behind Thrombus
Blood clots (or thrombi) form when strands of protein called fibrin accumulate in a blood vessel. In the heart, blood clots cause blockage of blood flow to muscle tissue. If blood flow is blocked, the oxygen supply to that tissue is cut off and it eventually dies. This can result in angina and heart attacks. Clots in chambers of the heart can mobilize to the brain. In the brain, blood clots also block blood and oxygen from reaching necessary areas, which can result in senility and/or stroke.1
Thrombolytic enzymes are normally generated in the endothelial cells of the blood vessels. As the body ages, production of these enzymes begins to decline, making blood more prone to coagulation. This mechanism can lead to cardiac or cerebral infarction, as well as other conditions. Since endothelial cells exist throughout the body, such as in the arteries, veins and lymphatic system, poor production of thrombolytic enzymes can lead to the development of thrombotic conditions virtually anywhere in the body.7
It has recently been revealed that thrombotic clogging of the cerebral blood vessels may be a cause of dementia. It has been estimated that sixty percent of senile dementia patients in Japan is caused by thrombus. Thrombotic diseases typically include cerebral hemorrhage, cerebral infarction, cardiac infarction and angina pectoris, and also include diseases caused by blood vessels with lowered flexibility, including senile dementia and diabetes (caused by pancreatic dysfunction). Hemorrhoids are considered a local thrombotic condition. If chronic diseases of the capillaries are also considered, then the number of thrombus related conditions may be much higher. Cardiac infarction patients may have an inherent imbalance in that their thrombolytic enzymes are weaker than their coagulant enzymes. Nattokinase holds great promise to support patients with such inherent weaknesses in a convenient and consistent manner, without side effects.1,6,7 Nattokinase is capable of directly and potently decomposing fibrin as well as activating pro-urokinase (endogenous).
Research In The United States
Dr. Martin Milner of the Center for Natural Medicine in Portland, Oregon and Dr. Kouhei Makise of the Imadeqawa Makise Clinica in Kyoto, Japan were able to launch a joint research project on nattokinase and write an extensive paper on their findings. "In all my years of research as a professor of cardiovascular and pulmonary medicine, natto and nattokinase represents the most exciting new development in the prevention and treatment of cardiovascular related diseases, "Dr. Milner said." We have finally found a potent natural agent that can thin and dissolve clots effectively, with relative safety and without side effects."1
Animal & Human Studies
Nattokinase has been the subject of 17 studies, including two small human trials. Dr. Sumi and his colleagues induced blood clots in male dogs, then orally administered either four capsules of nattokinase (250 mg per capsule) or four placebo capsules to each dog. Angiograms (X-rays of blood vessels) revealed that the dogs who received nattokinase regained normal blood circulation (free of the clot) within five hours of treatment. Blood clots in the dogs who received only placebo showed no sign of dissolving in the 18 hours following treatment.1,3
Researchers from Biotechnology Research Laboratories and JCR Pharmaceuticals Co. of Kobe, Japan, tested nattokinase's ability to dissolve a thrombus in the carotid arteries of rats. Animals treated with nattokinase regained 62 percent of blood flow, whereas those treated with plasmin regained just 15.8 percent of blood flow.1
Researchers from JCR Pharmaceuticals, Oklahoma State University, and Miyazaki Medical College tested nattokinase on 12 healthy Japanese volunteers (6 men and 6 women, between the ages of 21 and 55). They gave the volunteers 200 grams of natto (the food) before breakfast, then tracked fibrinolytic activity through a series of blood plasma tests. The tests indicated that the natto generated a heightened ability to dissolve blood clots: On average, the volunteers' ELT (a measure of how long it takes to dissolve a blood clot) dropped by 48 percent within two hours of treatment, and volunteers retained an enhanced ability to dissolve blood clots for 2 to 8 hours. As a control, researchers later fed the same amount of boiled soybeans to the same volunteers and tracked their fibrinolytic activity. The tests showed no significant change.1,3,6
The Benefits of Nattokinase on Blood Pressure
Traditionaly in Japan, Natto has been consumed not only for cardiovascular support, but also to lower blood pressure. In recent years, this traditional belief has been confirmed by several clinical trials. In 1995, researchers from Miyazaki Medical College and Kurashiki University of Science and Arts in Japan studied the effects of nattokinase on blood pressure in both animal and human subjects (see below). In addition, the researchers confirmed the presence of inhibitors of angiotensin converting enzyme (ACE), which converts angiotensin I to its active form angiotensin II within the test extract, which consisted of 80% ethanol extract of lyophilized viscous materials of natto. ACE causes blood vessels to narrow and blood pressure to rise - by inhibiting ACE, nattokinase has a lowering effect on blood pressure.1,2
Animal Study
After a single intraperitoneal administration of 400-450 grams of the test extract (equivalent to 25 mg of natto food) into male Wister rats, systolic blood pressure (SBP) significantly decreased from 166 + mmHg to 145 + 24 mmHg in just two hours (p<0.05), and decreased further to 144 + 27 mmHg in 3 hours (p<0.05). On average, this data represents a 12.7 percent drop in SBP within two hours.1,2
Human Study
The same natto extract was then tested on human volunteers with high blood pressure. Blood pressure levels were measured after 30 grams of lyophilized extract (equivalent to 200 grams of natto food) was administered orally for 4 consecutive days. In 4 out of 5 volunteers, the systolic blood pressure (SBP) decreased on average from 173.8 + 20.5 mmHg to 154.8 + 12.6 mmHg. Diastolic blood pressure (DBP) decreased on average from 101.0 + 11.4 mmHg to 91.2 + 6.6 mmHg. On average, this data represents a 10.9 percent drop in SBP and a 9.7 percent drop in DBP.1,2,6
Conclusion
The traditional Japanese food Natto has been used safely for over 1000 years. The potent fibrinolytic enzyme nattokinase appears to be safe based upon the long-term traditional use of this food. Nattokinase has many benefits including convenience of oral administration, confirmed efficacy, prolonged effects, cost effectiveness, and can be used preventatively. It is a naturally occurring, food based dietary supplement that has demonstrated stability in the gastrointestinal tract, as well as to changes in pH and temperature.
Glossary of Terms:
Cardiac Infarction: Heart attack.
Cerebral Infarction: Stroke.
Fibrin: A whitish, filamentous protein formed by the action of thrombin on fibrinogen and makes up part of coagulum or blood clots.
Fibrinolytic: Pertaining to or causing the breaking up of blood clots.
Infarction: Cardiac or cerebral tissue death due to failure of blood supply to the area usually caused by a blood clot.
Plasmin: An endogenously produced fibrinolytic enzyme.
Plasminogen: A precursor to plasmin. A protein found in many tissues and body fluids.
Thrombus: A blood clot that obstructs a blood vessel or a cavity of the heart.
Thrombolytic: Pertaining to or causing the breaking up of a thrombus.
TPA: Tissue plasminogen activator.
t-PAs: The most commonly used thrombolytic drugs including activase, urokinase, and streptokinase.
Urokinase: An endogenously produced thrombolytic enzyme & also a commonly used thrombolytic drug given intravenously to cardiac and cerbral infarction patients.
A mutant of Bacillus subtilis IMR-NK1, which is used for the production of domestic "natto" in Taiwan, produced high fibrinolytic enzyme activity by solid-state fermentation using wheat bran as medium.
Purification and characterization of a fibrinolytic enzyme produced from Bacillus sp. strain CK 11-4 screened from Chungkook-Jang.
Nattokinase is a new fibrinolytic enzyme which cleaves directly cross-linked fibrin in vitro. In this study, we investigated the thrombolytic effect of nattokinase on a thrombus in the common carotid artery of rat in which the endothelial cells of the vessel wall were injured by acetic acid. When a section of occluded vessel was stained for CD61 antigen by immunofluorescence utilizing a monoclonal antibody, the antigen was localized around the surface of the occluded blood vessels. This result suggests that the occlusive thrombosis was caused by platelet aggregation. In addition, thrombolysis with urokinase (UK; 50000 IU/kg, i.v.) or tissue plasminogen activator (tPA; 13300 IU/kg, i.v.) in our model was observed to restore the blood flow over a 60 min monitoring period. The results indicate that our chemically induced model is useful for screening and evaluating a thrombolytic agent. We evaluated the thrombolytic activity of nattokinase using this model and compared it with fibrino(geno)lytic enzyme, plasmin or elastase. On a molar basis, the recovery of the arterial blood flow with nattokinase, plasmin and elastase were 62.0 +/- 5.3%, 15.8 +/- 0.7% and 0%, respectively. The results indicate that the thrombolytic activity of nattokinase is stronger than that of plasmin or elastase in vivo.
Intraduodenal administration of nattokinase (NK) at a dose of 80 mg/kg, resulted in the degradation of fibrinogen in plasma suggesting transport of NK across the intestinal tract in normal rats. The action of NK on the cleavage of fibrinogen in the plasma from blood samples drawn at intervals after intraduodenal administration of the enzyme was investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis with an anti-fibrinogen gamma chain antibody. In parallel with the degradation process, plasma recalcification times were remarkably prolonged NK was also detected in the plasma from blood samples drawn 3 and 5 h after administration of the enzyme by SDS-PAGE and Western blotting analysis with an anti-NK antibody. The results indicate that NK is absorbed from the rat intestinal tract and that NK cleaves fibrinogen in plasma after intraduodenal administration of the enzyme.
Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular soybean fermented food in Japan.
A strong fibrinolytic enzyme (nattokinase) was purified from the vegetable cheese natto. Nattokinase was extracted from natto with saline and isolated by sequential use of hydrophobic chromatography. The isolated protein gave a single sharp band on SDS-PAGE either before or after reduction. The sequence, as determined by automated Edman degradation of the uncleaved molecule and its enzymatically derived peptide, consisted of a total 275 amino acid residues (M.W = 27,728) and exhibited a high homology with the subtilisins.
Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase.
The existence of a potent fibrinolytic enzyme (nattokinase, NK) in the traditional fermented food called 'natto', was reported by us previously. It was confirmed that oral administration of NK (or natto) produced a mild and frequent enhancement of the fibrinolytic activity in the plasma, as indicated by the fibrinolytic parameters, and the production of tissue plasminogen activator. NK capsules were also administered orally to dogs with experimentally induced thrombosis, and lysis of the thrombi was observed by angiography. The results obtained suggest that NK represents a possible compound for use not only in the treatment of embolism but also in the prevention of the disease, since NK has a proven safety and can be massproduced.
A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet.
A strong fibrinolytic activity was demonstrated in the vegetable cheese Natto, which is a typical soybean food eaten in Japan. The average activity was calculated at about 40 CU (plasmin units)/g wet weight. This novel fibrinolytic enzyme, named nattokinase, was easily extracted with saline. Nattokinase not only digested fibrin but also the plasmin substrate H-D-Val-Leu-Lys-pNA (S-2251).
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
It is imperative that Nattokinase is processed and stored by specific guideline to maintain maximum results in the body.
For further help go to Serraflazyme, an extraordinary enzyme - Ecological Formulas (Cardiovascular Research) - http://www.healingedge.net/store/ecological-ss8.html#363
Isolated, purified and encapsulated nattokinase, an enzyme derived from boiled soybeans and Bacillus subtilis natto. Nattokinase NSK-SD® was the first nattokinase introduced into the US market, and it has established standardization and quality levels for all nattokinase, with comprehensive safety studies and proven potency. It is vegetarian, non-irradiated, and free of vitamin K2. NSK-SD® has two Japanese and three U.S. patents, and is recognized by the JHFA (Japan Health and Nutrition Food Authorization) and JNKA (Japan Nattokinase Association) as authentic nattokinase. Each batch is tested to ensure potency. NSK-SD® is a trademark of Japan BioScience Laboratory.
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/*
* refclock_zyfer - clock driver for the Zyfer GPSTarplus Clock
*
* Harlan Stenn, Jan 2002
*/
#include "config.h"
#include "ntp.h"
#include "ntpd.h"
#include "ntp_io.h"
#include "ntp_refclock.h"
#include "ntp_stdlib.h"
#include <stdio.h>
#include <ctype.h>
#include <termios.h>
/*
* This driver provides support for the TOD serial port of a Zyfer GPStarplus.
* This clock also provides PPS as well as IRIG outputs.
* Precision is limited by the serial driver, etc.
*
* If I was really brave I'd hack/generalize the serial driver to deal
* with arbitrary on-time characters. This clock *begins* the stream with
* `!`, the on-time character, and the string is *not* EOL-terminated.
*
* Configure the beast for 9600, 8N1. While I see leap-second stuff
* in the documentation, the published specs on the TOD format only show
* the seconds going to '59'. I see no leap warning in the TOD format.
*
* The clock sends the following message once per second:
*
* !TIME,2002,017,07,59,32,2,4,1
* YYYY DDD HH MM SS m T O
*
* ! On-time character
* YYYY Year
* DDD 001-366 Day of Year
* HH 00-23 Hour
* MM 00-59 Minute
* SS 00-59 Second (probably 00-60)
* m 1-5 Time Mode:
* 1 = GPS time
* 2 = UTC time
* 3 = LGPS time (Local GPS)
* 4 = LUTC time (Local UTC)
* 5 = Manual time
* T 4-9 Time Figure Of Merit:
* 4 x <= 1us
* 5 1us < x <= 10 us
* 6 10us < x <= 100us
* 7 100us < x <= 1ms
* 8 1ms < x <= 10ms
* 9 10ms < x
* O 0-4 Operation Mode:
* 0 Warm-up
* 1 Time Locked
* 2 Coasting
* 3 Recovering
* 4 Manual
*
*/
/*
* Interface definitions
*/
#define DEVICE "/dev/zyfer%d" /* device name and unit */
#define SPEED232 B9600 /* uart speed (9600 baud) */
#define PRECISION (-20) /* precision assumed (about 1 us) */
#define REFID "GPS\0" /* reference ID */
#define NAME "ZYFER" /* shortname */
#define DESCRIPTION "Zyfer GPStarplus" /* WRU */
#define LENZYFER 29 /* timecode length */
/*
* Unit control structure
*/
struct zyferunit {
uint8_t Rcvbuf[LENZYFER + 1];
uint8_t polled; /* poll message flag */
int pollcnt;
int Rcvptr;
};
/*
* Function prototypes
*/
static bool zyfer_start (int, struct peer *);
static void zyfer_receive (struct recvbuf *);
static void zyfer_poll (int, struct peer *);
/*
* Transfer vector
*/
struct refclock refclock_zyfer = {
NAME, /* basename of driver */
zyfer_start, /* start up driver */
NULL, /* shut down driver in the standard way */
zyfer_poll, /* transmit poll message */
NULL, /* not used (old zyfer_control) */
NULL, /* initialize driver (not used) */
NULL /* timer - not used */
};
/*
* zyfer_start - open the devices and initialize data for processing
*/
static bool
zyfer_start(
int unit,
struct peer *peer
)
{
struct zyferunit *up;
struct refclockproc *pp;
int fd;
char device[20];
/*
* Open serial port.
* Something like LDISC_ACTS that looked for ! would be nice...
*/
snprintf(device, sizeof(device), DEVICE, unit);
fd = refclock_open(peer->cfg.path ? peer->cfg.path : device,
peer->cfg.baud ? peer->cfg.baud : SPEED232,
LDISC_RAW);
if (fd <= 0)
/* coverity[leaked_handle] */
return false;
msyslog(LOG_NOTICE, "REFCLOCK: zyfer(%d) fd: %d", unit, fd);
/*
* Allocate and initialize unit structure
*/
up = emalloc_zero(sizeof(struct zyferunit));
pp = peer->procptr;
pp->io.clock_recv = zyfer_receive;
pp->io.srcclock = peer;
pp->io.datalen = 0;
pp->io.fd = fd;
if (!io_addclock(&pp->io)) {
close(fd);
pp->io.fd = -1;
free(up);
return false;
}
pp->unitptr = up;
/*
* Initialize miscellaneous variables
*/
peer->precision = PRECISION;
pp->clockname = NAME;
pp->clockdesc = DESCRIPTION;
memcpy((char *)&pp->refid, REFID, REFIDLEN);
peer->sstclktype = CTL_SST_TS_UHF;
up->pollcnt = 2;
up->polled = 0; /* May not be needed... */
return true;
}
/*
* zyfer_receive - receive data from the serial interface
*/
static void
zyfer_receive(
struct recvbuf *rbufp
)
{
struct zyferunit *up;
struct refclockproc *pp;
struct peer *peer;
int tmode; /* Time mode */
int tfom; /* Time Figure Of Merit */
int omode; /* Operation mode */
uint8_t *p;
peer = rbufp->recv_peer;
pp = peer->procptr;
up = pp->unitptr;
p = (uint8_t *) &rbufp->recv_buffer;
/*
* If lencode is 0:
* - if *rbufp->recv_buffer is !
* - - call refclock_gtlin to get things going
* - else flush
* else stuff it on the end of lastcode
* If we don't have LENZYFER bytes
* - wait for more data
* Crack the beast, and if it's OK, process it.
*
* We use refclock_gtlin() because we might use LDISC_CLK.
*
* Under FreeBSD, we get the ! followed by two 14-byte packets.
*/
if (pp->lencode >= LENZYFER)
pp->lencode = 0;
if (!pp->lencode) {
if (*p == '!')
pp->lencode = refclock_gtlin(rbufp, pp->a_lastcode,
BMAX, &pp->lastrec);
else
return;
} else {
memcpy(pp->a_lastcode + pp->lencode, p, rbufp->recv_length);
pp->lencode += (int)rbufp->recv_length;
pp->a_lastcode[pp->lencode] = '\0';
}
if (pp->lencode < LENZYFER)
return;
record_clock_stats(peer, pp->a_lastcode);
/*
* We get down to business, check the timecode format and decode
* its contents. If the timecode has invalid length or is not in
* proper format, we declare bad format and exit.
*/
if (pp->lencode != LENZYFER) {
refclock_report(peer, CEVNT_BADTIME);
return;
}
/*
* Timecode sample: "!TIME,2002,017,07,59,32,2,4,1"
*/
if (sscanf(pp->a_lastcode, "!TIME,%4d,%3d,%2d,%2d,%2d,%d,%d,%d",
&pp->year, &pp->day, &pp->hour, &pp->minute, &pp->second,
&tmode, &tfom, &omode) != 8) {
refclock_report(peer, CEVNT_BADREPLY);
return;
}
if (tmode != 2) {
refclock_report(peer, CEVNT_BADTIME);
return;
}
/* Should we make sure tfom is 4? */
if (omode != 1) {
pp->leap = LEAP_NOTINSYNC;
return;
}
if (!refclock_process(pp)) {
refclock_report(peer, CEVNT_BADTIME);
return;
}
/*
* Good place for record_clock_stats()
*/
up->pollcnt = 2;
if (up->polled) {
up->polled = 0;
refclock_receive(peer);
}
}
/*
* zyfer_poll - called by the transmit procedure
*/
static void
zyfer_poll(
int unit,
struct peer *peer
)
{
struct zyferunit *up;
struct refclockproc *pp;
UNUSED_ARG(unit);
/*
* We don't really do anything here, except arm the receiving
* side to capture a sample and check for timeouts.
*/
pp = peer->procptr;
up = pp->unitptr;
if (!up->pollcnt) {
refclock_report(peer, CEVNT_TIMEOUT);
} else {
up->pollcnt--;
}
pp->polls++;
up->polled = 1;
}
|
/*
* Licensed to the Apache Software Foundation (ASF) under one
* or more contributor license agreements. See the NOTICE file
* distributed with this work for additional information
* regarding copyright ownership. The ASF licenses this file
* to you under the Apache License, Version 2.0 (the
* "License"); you may not use this file except in compliance
* with the License. You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing,
* software distributed under the License is distributed on an
* "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY
* KIND, either express or implied. See the License for the
* specific language governing permissions and limitations
* under the License.
*/
package org.apache.syncope.client.console.rest;
import java.io.Serializable;
import java.util.Comparator;
import java.util.List;
import java.util.Optional;
import java.util.stream.Collectors;
import org.apache.syncope.common.lib.policy.PolicyTO;
import org.apache.syncope.common.lib.types.PolicyType;
import org.apache.syncope.common.rest.api.service.PolicyService;
/**
* Console client for invoking Rest Policy services.
*/
public class PolicyRestClient extends BaseRestClient {
private static final long serialVersionUID = -1392090291817187902L;
private static final PolicyComparator COMPARATOR = new PolicyComparator();
public static <T extends PolicyTO> T getPolicy(final PolicyType type, final String key) {
T policy = null;
try {
policy = getService(PolicyService.class).read(type, key);
} catch (Exception e) {
LOG.warn("No policy found for id {}", key, e);
}
return policy;
}
@SuppressWarnings("unchecked")
public static <T extends PolicyTO> List<T> getPolicies(final PolicyType type) {
try {
return getService(PolicyService.class).<T>list(type).stream().
sorted(COMPARATOR).
collect(Collectors.toList());
} catch (Exception ignore) {
LOG.debug("No policy found", ignore);
return List.of();
}
}
public static <T extends PolicyTO> void createPolicy(final PolicyType type, final T policy) {
getService(PolicyService.class).create(type, policy);
}
public static <T extends PolicyTO> void updatePolicy(final PolicyType type, final T policy) {
getService(PolicyService.class).update(type, policy);
}
public static void delete(final PolicyType type, final String key) {
getService(PolicyService.class).delete(type, key);
}
private static class PolicyComparator implements Comparator<PolicyTO>, Serializable {
private static final long serialVersionUID = -4921433085213223115L;
@Override
public int compare(final PolicyTO left, final PolicyTO right) {
return Optional.ofNullable(left).map(to -> Optional.ofNullable(right)
.map(policyTO -> to.getDescription().compareTo(policyTO.getDescription())).orElse(1)).orElse(-1);
}
}
}
|
The invention relates to camera housings and more specifically to the optical sealing of pressurized or hermetically sealed housings.
As the use of photographic and television cameras has expanded, including underwater monitoring, the need to protect the delicate elements of the camera from adverse environments of heat, cold, dust, and moisture has likewise increased. For many of these uses there have been provided rugged hermetically sealed camera housings, and for more hostile environments these housings are purged with a desiccated gas and pressurized above the outside environmental pressure so that any small amount of leakage will be from inside the housing to the outside environment, thus preventing ingestion of elements of the environment into the delicate camera mechanism.
In the case of camera housings which are hermetically sealed at atmospheric pressure there may be developed a positive internal pressure due to a reduced external pressure, such as caused by carrying the camera to a higher altitude. Additionally, an internal temperature rise will cause a concomitant pressure rise.
When for what ever reason positive internal pressure exists, there is a potential danger to the technician attempting to disassemble the housing wherein a sudden or explosive expansion or decompression may be triggered by removal of a retaining element such as a screw or snap-ring. To prevent such a possibility most camera housings are provided with a bleed valve which the technician should operate to bleed off any internal pressure. Because the bleed off procedure reduces the internal pressure until it approaches the outside pressure asymptotically, the technician may not detect the reduced but continued escaping gas flow and turn off the bleed valve too soon, thus leaving a residual internal pressure. Also the internal pressure is reduced isothermally, and after the bleed valve is turned off internal temperature stabilization may cause a residual internal pressure to be created.
Of even greater danger is the possibility of the technician forgetting to actuate the bleed valve. This is particularly a possibility in the case of a camera housing which has been sealed at atmospheric pressure and is therefor in the technician's view "unpressurized". However, as previously described such housings may very well contain a positive internal pressure.
Thus, because of the above and other reasons, difficulties have continued to exist in the opening of hermetically sealed camera housings for conducting normal maintenance on the camera elements contained therein. |
Q:
XamlBindingHelper Class
Can somebody provide an overview for use of the XamlBindingHelper class with examples? Specifically the GetDataTemplateComponent and SetDataTemplateComponent method.
A:
In the official document, it says
This class is for use in code that is generated by the XAML compiler.
This tells me that I should be able to find some reference of it in code-generated classes (.g.cs) by x:Bind, given there's not a single thread on the Internet that explains what exactly it does.
So I created a test UWP project with a ListView, and inside its ItemTemplate I threw in some x:Bind with x:Phase. After I compiled the project, I found some of its methods used inside my MainPage.g.cs -
XamlBindingHelper.ConvertValue
public static void Set_Windows_UI_Xaml_Controls_ItemsControl_ItemsSource(global::Windows.UI.Xaml.Controls.ItemsControl obj, global::System.Object value, string targetNullValue)
{
if (value == null && targetNullValue != null)
{
value = (global::System.Object) global::Windows.UI.Xaml.Markup.XamlBindingHelper.ConvertValue(typeof(global::System.Object), targetNullValue);
}
obj.ItemsSource = value;
}
Apparently the XamlBindingHelper.ConvertValue method is for converting values. I knew this already, as I used it in one of my recent answers on SO.
XamlBindingHelper.SuspendRendering & XamlBindingHelper.ResumeRendering
public int ProcessBindings(global::Windows.UI.Xaml.Controls.ContainerContentChangingEventArgs args)
{
int nextPhase = -1;
switch(args.Phase)
{
case 0:
nextPhase = 1;
this.SetDataRoot(args.Item);
if (!removedDataContextHandler)
{
removedDataContextHandler = true;
((global::Windows.UI.Xaml.Controls.StackPanel)args.ItemContainer.ContentTemplateRoot).DataContextChanged -= this.DataContextChangedHandler;
}
this.initialized = true;
break;
case 1:
global::Windows.UI.Xaml.Markup.XamlBindingHelper.ResumeRendering(this.obj4);
nextPhase = -1;
break;
}
this.Update_((global::System.String) args.Item, 1 << (int)args.Phase);
return nextPhase;
}
public void ResetTemplate()
{
this.bindingsTracking.ReleaseAllListeners();
global::Windows.UI.Xaml.Markup.XamlBindingHelper.SuspendRendering(this.obj4);
}
XamlBindingHelper.SuspendRendering & XamlBindingHelper.ResumeRendering look very interesting. They seem to be the key functions to enable ListView/GridView's incremental item rendering which helps improve the overall panning/scrolling experience.
So apart from x:DeferLoadingStrategy and x:Load(Creators Update), they are something else that could be used to improve your app performance.
IDataTemplateComponent & IDataTemplateExtension
However, I couldn't find anything related to GetDataTemplateComponent and SetDataTemplateComponent. I even tried to manually set this attached property in XAML but the get method always returned null.
And here's the interesting bit. I later found this piece of code in the generated class.
case 2: // MainPage.xaml line 13
{
global::Windows.UI.Xaml.Controls.Grid element2 = (global::Windows.UI.Xaml.Controls.Grid)target;
MainPage_obj2_Bindings bindings = new MainPage_obj2_Bindings();
returnValue = bindings;
bindings.SetDataRoot(element2.DataContext);
element2.DataContextChanged += bindings.DataContextChangedHandler;
global::Windows.UI.Xaml.DataTemplate.SetExtensionInstance(element2, bindings);
}
break;
The method DataTemplate.SetExtensionInstance looks very similar to XamlBindingHelper.SetDataTemplateComponent. It takes element2 which is the root Grid inside the ItemTemplate of my ListView, and an IDataTemplateExtension; where the latter takes an element and an IDataTemplateComponent. If you have a look at their definitions, their functionalities are very similar, which makes me think if DataTemplate.SetExtensionInstance is the replacement of XamlBindingHelper.SetDataTemplateComponent? I'd love to know if otherwise.
Unlike IDataTemplateComponent, you can get an instance of the IDataTemplateExtension in your code -
var firstItemContainer = (ListViewItem)MyListView.ContainerFromIndex(0);
var rootGrid = (Grid)firstItemContainer?.ContentTemplateRoot;
var dataTemplateEx = DataTemplate.GetExtensionInstance(rootGrid);
In my case, the dataTemplateEx is an instance of another generated class called MainPage_obj2_Bindings, where you have access to methods like ResetTemplate and ProcessBindings.
I assume they could be helpful if you were to build your own custom list controls, but other than that I just can't see why you would ever need them.
|
Memory Book
Memories of Father Locatelli
The House that Paul Built
Thursday, Jul. 15, 2010
As a faculty member, I’m grateful that Paul Locatelli did a hard job very well. Reading these memories of him is like reading a how-to manual for leadership: Attract good people. Help them define a common vision. Provide the resources that inspire them to do their best work. Resolve their disagreements as wisely as possible. Look inside and outside the walls for new ideas. Know your values and act on them. Pay the bills. Still, I’m left with questions. How, in this world, did he raise so much money to support Santa Clara’s vision of education? How did he maintain his cheerful optimism amidst the daily slings and arrows aimed at a university president? How do we advance the best of his life’s work through ours? Chad Raphael Associate Professor of Communication |
Tony Pulis issues warning to Dael Fry
The Middlesbrough manager was responding to the reported interest of several Premier League clubs in Boro defender Dael Fry.
Although he is in-form and improving every day, Dael Fry needs to stay at Middlesbrough FC if he is to continue his impressive development, according to Tony Pulis.
Fry, who has featured intermittently for Boro in the past couple of seasons, has really come of age this season to help turn Boro into one of the meanest defences in the Championship.
Apart from starring in his traditional role at centre-back, Fry has been a revelation at right-back, where he is deputising for the injured Ryan Shotton.
His remarkable performances haven’t gone unnoticed, though, with the likes of Liverpool, Tottenham, and Chelsea reportedly eyeing a move for the 21-year-old.
However, as far as his manager Tony Pulis is concerned, the youngster needs to keep his feet on the ground and be patient.
"I've worked in the Premiership and Dael is not ready yet," was Pulis' candid assessment.
"He's quick, he's strong. The problem with Dael, if you look, is the number of games he's played compared to what he should have played. It's the same with Tav and Wingy. I know Wingy went to Yeovil last year and they did a fantastic job with him.”
"We've got some good kids here and they'll have their chances."
Boro’s youngsters have been getting their fair share of chances this season – and they are taking it with both hands when ever given the opportunity.
Apart from Fry, the likes of Lewis Wing and Marcus Tavernier have both impressed Boro fans with their performances this term.
While Fry is set to remain at Boro at least until the end of this season, nothing could be said with certainty about the immediate future of the other two players. For, a large number of clubs would jump at the chance of signing either Tavernier or Wing on loan in January.
Still, as far as Pulis is concerned, all three of them need to stay put at Middlesbrough if they want more game time.
"We have to be careful with Tav, Wingy, and Dael, they're all young, they haven’t played as much football" said Pulis.
"Our kids haven't played as much as they should have, we have to be careful, but they're good players and they can be good players for this football club." |
Product Overview
Key Features & Specifications
Best-in-class power linearity of less than 1%, excellent SWR of mismatch uncertainty and highly accurate power repeatability
Accurate calibration and traceability to US National Institute of Standards and Technology (NIST)
SCPI codes compatible with 8480 series (option CFT)
Note: Option CFT is available as a replacement of legacy 8480 Series power sensors intended for cal factor manual entry and SCPI compatibility. Option CFT is not compatible with 43x and other obsolete power meters. |
Q:
Is there an example of forking and communicating with a subprocess in D?
How do you fork and communicate with a subprocess in D?
I think I'm pretty much looking for http://erdani.com/d/new-stdio/phobos-prerelease/std_process.html#pipeProcess but pipeProcess doesn't seem to be in D2.
I want to execute a child process and be able to read from its stdout and stderr, write to its stdin and receive notification of it exiting and its exit code.
What is the best way of doing this in D?
Thanks,
Chris.
A:
Eventually this functionality will be in Phobos, but for now, here's a class I tossed together: Pastebin link
You use it like this:
auto stream = new ProcessStream("ls -a");
// read, write, etc. from stream
|
Citation Nr: 0422229
Decision Date: 08/13/04 Archive Date: 08/20/04
DOCKET NO. 02-12 828 ) DATE
)
)
On appeal from the
Department of Veterans Affairs Regional Office in Waco, Texas
THE ISSUE
Entitlement to VA compensation benefits under 38 U.S.C.A
§ 1151 for residuals of surgical treatment at a VA medical
facility on March 2, 1989.
REPRESENTATION
Appellant represented by: Texas Veterans Commission
WITNESS AT HEARING ON APPEAL
The veteran
ATTORNEY FOR THE BOARD
L. Spear Ethridge, Counsel
INTRODUCTION
The veteran had active military service from March 1965 to
March 1967.
This matter comes before the Board of Veterans' Appeals
(Board) on appeal from an April 2002 rating decision of the
Department of Veterans Affairs (VA) Regional Office (RO) in
Waco, Texas, that denied the above claim. In March 2003, the
veteran testified before the RO during a personal hearing.
FINDING OF FACT
Additional disability (claimed as residuals, status post
excision, left salivary gland) is not the result of VA
hospital care, medical or surgical treatment, or examination.
CONCLUSION OF LAW
Entitlement to VA compensation under 38 U.S.C.A § 1151 for
residuals of surgical treatment of excision, left salivary
gland, performed at a VA medical facility in March 1989 is
not warranted. 38 U.S.C.A. § 1151 (West 2002); 38 C.F.R.
§ 3.358 (2003).
REASONS AND BASES FOR FINDING AND CONCLUSION
As a preliminary matter, the Board finds that VA has
satisfied its duties to inform and assist the veteran under
the Veterans Claims Assistance Act of 2000 (VCAA). In a
March 2001 letter, the RO notified the veteran of the
information and evidence needed to substantiate and complete
her claim, and of what part of that evidence she was to
provide and what part VA would attempt to obtain for her.
She was also asked to submit evidence and/or information in
her possession to the RO. 38 U.S.C.A. § 5103(a) (West 2002);
38 C.F.R. § 3.159(b)(1) (2003); Quartuccio v. Principi, 16
Vet. App. 183, 187 (2002). The content and timing of the
March 2001 letter complied with the requirements of
38 U.S.C.A. § 5103(a) and 38 C.F.R. § 3.159(b). See
Pelegrini v. Principi, No. 01-944 (U.S. Vet. App. June 24,
2004).
Under the VCAA, VA also has a duty to assist claimants in
obtaining evidence needed to substantiate a claim. 38
U.S.C.A. § 5103A (West 2002); 38 C.F.R. § 3.159(c) (2003).
In this case, the veteran's VA medical records from the
surgery in question are on file. The RO has obtained all VA
medical records identified by the veteran. 38 U.S.C.A.
§ 5103A(c) (West 2002); 38 C.F.R. § 3.159(c)(2), (3) (2003).
All indicated private medical records have also been
obtained. The veteran testified at a personal hearing in
March 2003.
Assistance shall also include providing a medical examination
or obtaining a medical opinion when such an examination or
opinion is necessary to make a decision on the claim. 38
U.S.C.A. § 5103A(d); 38 C.F.R. § 3.159(c)(4). Here, the
veteran has not been afforded a VA medical examination
concerning her claim. However, the U.S. Court of Appeals for
the Federal Circuit has held that in order for a VA
examination to be necessary, "the veteran is required to
show some causal connection between his disability and his
military service. A disability alone is not enough." Wells
v. Principi, 326 F.3d 1381, 1383-84 (Fed. Cir. 2003). The
same principle holds true here, in that the veteran must show
some causal connection between the residuals she is claiming
and her surgery at VA in March 1989. Thus, a VA examination
and/or opinion is not warranted in the present case, based on
the evidence of record.
For the reasons set forth above, and given the facts of this
case, the Board finds that no further notification or
development action is necessary. 38 U.S.C.A. § 5103A(d)
(West 2002); 38 C.F.R. § 3.159(c)(4) (2003).
The veteran claims entitlement to compensation for residuals
of surgical treatment excision, left salivary gland. The
provisions of 38 U.S.C.A. § 1151 were amended, effective
October 1, 1997, to include the requirement of fault,
requiring that additional disability be the result of
carelessness, negligence, lack of proper skill, error in
judgment or similar fault on the part of VA in furnishing
care, or an event not reasonably foreseeable. See
38 U.S.C.A. § 1151 (West 2002). Here, the veteran's claim
for compensation under the provisions of 38 U.S.C.A. § 1151
was received by the RO in February 2001; therefore, the
regulations effective on October 1, 1997 apply in this case.
The law provides that a disability is a qualifying additional
disability if the disability was not the result of the
veteran's own willful misconduct and, the disability was
caused by hospital care, medical or surgical treatment, or
examination, and the proximate cause of the disability was
carelessness, negligence, lack of proper skill, error in
judgment, or similar instance of fault on the part of VA in
furnishing the hospital care, medical or surgical treatment,
or examination; or an event not reasonably foreseeable. 38
U.S.C.A. § 1151 (West 2002).
Although claims for 38 U.S.C.A. § 1151 benefits are not based
upon actual service connection, there are similarities in
their adjudication. Boeck v. Brown, 6 Vet. App. 14, 16-17
(1993). A claim for 38 U.S.C.A. § 1151 benefits must be
supported by medical evidence of a current disability and
medical evidence that the current disability resulted from VA
hospitalization, medical examination, or treatment.
The applicable regulation provides that where it is
determined that there is additional disability resulting from
a disease or injury or an aggravation of an existing disease
or injury suffered as a result of hospitalization, medical or
surgical treatment, or examination, compensation will be
payable for such additional disability. 38 C.F.R. § 3.358(a)
(2003).
The regulation provides that, as applied to medical or
surgical treatment in determining that additional disability
exists, the physical condition prior to the disease or injury
will be the condition which the specific medical or surgical
treatment was designed to relieve. 38 C.F.R. § 3.358(b)(1)
(2003). It also provides that compensation will not be
payable for the continuance or natural progress of disease or
injuries for which the hospital care, medical or surgical
treatment, or examination, was authorized. 38 C.F.R.
§ 3.358(b)(2) (2003).
The regulation provides that, in determining whether such
additional disability resulted from a disease or an injury or
an aggravation of an existing disease or injury suffered as a
result of hospitalization, medical or surgical treatment, or
examination, the following considerations will govern:
(1) It will be necessary to show that the
additional disability is actually the result of
such disease or injury or an aggravation of an
existing disease or injury and not merely
coincidental therewith.
(2) The mere fact that aggravation occurred will
not suffice to make the additional disability
compensable in the absence of proof that it
resulted from disease or injury or an aggravation
of an existing disease or injury suffered as the
result of hospitalization, medical or surgical
treatment, or examination.
(3) Compensation is not payable for the necessary
consequences of medical or surgical treatment or
examination properly administered with the express
or implied consent of the veteran.
(4) When the proximate cause of the injury
suffered was the veteran's willful misconduct or
failure to follow instructions, it will bar the
veteran from receipt of compensation hereunder
except in the case of incompetent veterans.
38 C.F.R. § 3.358(c) (2003).
When all the evidence is assembled, VA is responsible for
determining whether the evidence supports the claim or is in
relative equipoise, with the appellant prevailing in either
event, or whether a preponderance of the evidence is against
a claim, in which case, the claim is denied. Gilbert v.
Derwinski, 1 Vet. App. 49 (1990).
During her personal hearing in March 2003, the veteran
testified that if she had been allowed to go to the ear, nose
and throat (ENT) clinic at the Dallas VA Medical Center at an
earlier date, the surgery to remove her left salivary gland
on March 2, 1989, would not have been necessary. She
maintains that she sought treatment on 4 occasions in
December 1988 and January 1989 for a sore throat, before she
was permitted to be seen at the ENT clinic on March 1, 1989.
It was at that time that the left-sided swelling in her
throat necessitated surgical removal of the salivary gland,
the next day, at the VA Medical Center in Dallas, Texas. She
also maintained that this surgery resulted in dental and
sinus disabilities.
VA treatment records show that in January 1985 and December
1986, the veteran was treated for sialoadenitis. In January
1988, she sought treatment for, among other things, swollen
mandibular glands.
On January 7, 1989, the veteran presented to VA with
complaints of pain in both sides of the mandible, and
difficulty swallowing. On January 19, 1989, she presented to
VA with a left neck knot with pain and swelling. A
consultation sheet from the emergency room to the ear, nose
and throat section, showed a diagnosis of adenitis to rule
out gland stones. On January 23, 1989, the veteran was seen
at VA for status post excision of stones of the left
submandibular gland one year prior, now with a firm, but
mobile gland.
In a March 1, 1989, preoperative report, from the VA Medical
Center in Dallas, Texas, it is noted that the veteran
presented with documented stones milked from the left
warthins duct. She had had multiple episodes of acute
submandibular sialoadenitis. The physician's admitting slip
shows that she was admitted under urgent circumstances for
sialoadenitis.
On March 2, 1989, the veteran underwent a left submandibular
gland excision. The operation report shows that she
presented with recurrent acute left submandibular
sialoadenitis, which had been treated with local sialagogues,
heat application, and antibiotic treatment. She had salivary
calculi milked from her left Wharton's duct on several visits
to the hospital, and had had two previous recent infections
requiring antibiotic treatment. The physician reported that
the veteran tolerated the procedure extremely well and she
was taken to the recovery room awake and in good condition.
She had completely normal facial nerve function, including
excellent marginal mandibular function at the conclusion of
the procedure. The final diagnosis was recurrent acute left
submandibular sialoadentis.
Post-operative notes dated in March 2, 1989, reveal that the
veteran was alert and oriented. On March 3, 1989, she had
difficulty swallowing. She was discharged to go home on
antibiotics and Tylenol on March 3, 1989. The tissue
examination diagnosis was submandibular gland (left),
sirolithiasis and sialordentitis with fibrosis, chronic
inflammation and grandular atrophy. On March 17, 1989, the
veteran was described as doing well, with essentially normal
examination.
In April 1989, the veteran presented to VA with fever and
chills and pharyngeal pain. Later in April, examination of
the pharynx was normal. This was diagnosed as tonsillitis
for which the veteran had a tonsillectomy in June 1989.
The veteran sought treatment for sinus congestion in December
1993. The assessment was rule out sinusitis. In January
1994, she was diagnosed as having questionable allergic
sinusitis. VA treatment notes dated in December 1995 and
April 1996 show that she was diagnosed as having allergic
sinusitis and chronic sinusitis, respectively.
Private treatment records from Baylor College of Dentistry
show the veteran's history and dental treatment there from
September 2001 until December 2001. On her clinical record,
it was noted that there was no significant medical history.
It was remarked that there was decreased saliva production
due to removal of salivary gland. She had chronic
generalized gingivitis, periodontis, calculus, stain and
plaque on the teeth. In September 2001, it was noted that
she underwent consultation for extraction of teeth numbered
22 to 28 due to severe decay, and that there was no
significant medical history. In October 2001, teeth 22-28,
and 2, were extracted and on number 2 an alveoloplasty was
done. In December 2001, dentures were completed. She was
seen in January and February 2002 for adjustments.
The medical evidence of record is negative as to a finding of
a causal relationship between the veteran's current sinusitis
and dental problems and the surgical removal of her salivary
gland in March 1989. Nor is there any competent medical
evidence of record showing that prior treatment by VA
necessitated the removal of the veteran's salivary gland in
March 1989.
The evidence does not reveal any basis upon which the Board
can reasonably conclude that any carelessness, negligence,
lack of proper skill, error in judgment or similar instance
of fault in VA's care was the proximate cause of any
additional disability. Nor does the evidence reveal that any
additional disability was proximately caused by an event not
reasonably foreseeable. In this regard, the Board notes that
Baylor dental records show in a remark section that there was
decreased saliva due to removal of salivary gland, but there
is no indication that this was related to the veteran's
current dental problems. The veteran does not identify any
act or omission on the part of VA that was careless,
negligent, lacking in proper skill, erroneous in judgment, or
the result of similar instance of fault during the March 2,
1989 surgery. The Board can find no such act from this
evidence. Further, the veteran has not provided any evidence
that she has any additional dental or other disability
related to her excision of the left salivary gland. The
records she has submitted show that her teeth were extracted
in 2001 due to severe decay and that her sinusitis is
allergic in origin. The numerous outpatient treatment
records are referable to other ailments.
Consequently, the Board finds that, upon consideration of the
available records, including the private and VA records, the
veteran's contentions including her personal hearing
testimony, and the absence of evidence suggesting a different
outcome, the preponderance of the evidence is against the
claim. The veteran's own contentions are not competent.
There is no indication that she possesses the requisite
medical knowledge or education to render a probative opinion
involving medical diagnosis or medical causation. See
Espiritu v. Derwinski, 2 Vet. App. 492, 494 (1992).
The criteria for an award of compensation benefits for
residuals, status post excision, left salivary gland under 38
U.S.C.A. § 1151 have not been met. The Board has considered
the doctrine of reasonable doubt, but finds that the record
does not provide an approximate balance of negative and
positive evidence on the merits. 38 C.F.R. § 3.102 (2003).
ORDER
Entitlement to VA compensation benefits under 38 U.S.C.A
§ 1151 for residuals of surgical treatment at a VA medical
facility on March 2, 1989, is denied.
____________________________________________
P. M. DILORENZO
Veterans Law Judge, Board of Veterans' Appeals
Department of Veterans Affairs
YOUR RIGHTS TO APPEAL OUR DECISION
The attached decision by the Board of Veterans' Appeals (BVA or Board) is
the final decision for all issues addressed in the "Order" section of the
decision. The Board may also choose to remand an issue or issues to the
local VA office for additional development. If the Board did this in your
case, then a "Remand" section follows the "Order." However, you cannot
appeal an issue remanded to the local VA office because a remand is not a
final decision. The advice below on how to appeal a claim applies only to
issues that were allowed, denied, or dismissed in the "Order."
If you are satisfied with the outcome of your appeal, you do not need to do
anything. We will return your file to your local VA office to implement
the BVA's decision. However, if you are not satisfied with the Board's
decision on any or all of the issues allowed, denied, or dismissed, you
have the following options, which are listed in no particular order of
importance:
? Appeal to the United States Court of Appeals for Veterans Claims
(Court)
? File with the Board a motion for reconsideration of this decision
? File with the Board a motion to vacate this decision
? File with the Board a motion for revision of this decision based on
clear and unmistakable error.
Although it would not affect this BVA decision, you may choose to also:
? Reopen your claim at the local VA office by submitting new and
material evidence.
There is no time limit for filing a motion for reconsideration, a motion to
vacate, or a motion for revision based on clear and unmistakable error with
the Board, or a claim to reopen at the local VA office. None of these
things is mutually exclusive - you can do all five things at the same time
if you wish. However, if you file a Notice of Appeal with the Court and a
motion with the Board at the same time, this may delay your case because of
jurisdictional conflicts. If you file a Notice of Appeal with the Court
before you file a motion with the BVA, the BVA will not be able to consider
your motion without the Court's permission.
How long do I have to start my appeal to the Court? You have 120 days from
the date this decision was mailed to you (as shown on the first page of
this decision) to file a Notice of Appeal with the United States Court of
Appeals for Veterans Claims. If you also want to file a motion for
reconsideration or a motion to vacate, you will still have time to appeal
to the Court. As long as you file your motion(s) with the Board within 120
days of the date this decision was mailed to you, you will then have
another 120 days from the date the BVA decides the motion for
reconsideration or the motion to vacate to appeal to the Court. You should
know that even if you have a representative, as discussed below, it is your
responsibility to make sure that your appeal to Court is filed on time.
How do I appeal to the United States Court of Appeals for Veterans Claims?
Send your Notice of Appeal to the Court at:
Clerk, U.S. Court of Appeals for Veterans Claims
625 Indiana Avenue, NW, Suite 900
Washington, DC 20004-2950
You can get information about the Notice of Appeal, the procedure for
filing a Notice of Appeal, the filing fee (or a motion to waive the filing
fee if payment would cause financial hardship), and other matters covered
by the Court's rules directly from the Court. You can also get this
information from the Court's web site on the Internet at
www.vetapp.uscourts.gov, and you can download forms directly from that
website. The Court's facsimile number is (202) 501-5848.
To ensure full protection of your right of appeal to the Court, you must
file your Notice of Appeal with the Court, not with the Board, or any other
VA office.
How do I file a motion for reconsideration? You can file a motion asking
the BVA to reconsider any part of this decision by writing a letter to the
BVA stating why you believe that the BVA committed an obvious error of fact
or law in this decision, or stating that new and material military service
records have been discovered that apply to your appeal. If the BVA has
decided more than one issue, be sure to tell us which issue(s) you want
reconsidered. Send your letter to:
Director, Management and Administration (014)
Board of Veterans' Appeals
810 Vermont Avenue, NW
Washington, DC 20420
VA
FORM
JUN
2003
(RS)
4597
Page
1
CONTINUED
Remember, the Board places no time limit on filing a motion for
reconsideration, and you can do this at any time. However, if you also plan
to appeal this decision to the Court, you must file your motion within 120
days from the date of this decision.
How do I file a motion to vacate? You can file a motion asking the BVA to
vacate any part of this decision by writing a letter to the BVA stating why
you believe you were denied due process of law during your appeal. For
example, you were denied your right to representation through action or
inaction by VA personnel, you were not provided a Statement of the Case or
Supplemental Statement of the Case, or you did not get a personal hearing
that you requested. You can also file a motion to vacate any part of this
decision on the basis that the Board allowed benefits based on false or
fraudulent evidence. Send this motion to the address above for the
Director, Management and Administration, at the Board. Remember, the Board
places no time limit on filing a motion to vacate, and you can do this at
any time. However, if you also plan to appeal this decision to the Court,
you must file your motion within 120 days from the date of this decision.
How do I file a motion to revise the Board's decision on the basis of clear
and unmistakable error? You can file a motion asking that the Board revise
this decision if you believe that the decision is based on "clear and
unmistakable error" (CUE). Send this motion to the address above for the
Director, Management and Administration, at the Board. You should be
careful when preparing such a motion because it must meet specific
requirements, and the Board will not review a final decision on this basis
more than once. You should carefully review the Board's Rules of Practice
on CUE, 38 C.F.R. 20.1400 -- 20.1411, and seek help from a qualified
representative before filing such a motion. See discussion on
representation below. Remember, the Board places no time limit on filing a
CUE review motion, and you can do this at any time.
How do I reopen my claim? You can ask your local VA office to reopen your
claim by simply sending them a statement indicating that you want to reopen
your claim. However, to be successful in reopening your claim, you must
submit new and material evidence to that office. See 38 C.F.R. 3.156(a).
Can someone represent me in my appeal? Yes. You can always represent
yourself in any claim before VA, including the BVA, but you can also
appoint someone to represent you. An accredited representative of a
recognized service organization may represent you free of charge. VA
approves these organizations to help veterans, service members, and
dependents prepare their claims and present them to VA. An accredited
representative works for the service organization and knows how to prepare
and present claims. You can find a listing of these organizations on the
Internet at: www.va.gov/vso. You can also choose to be represented by a
private attorney or by an "agent." (An agent is a person who is not a
lawyer, but is specially accredited by VA.)
If you want someone to represent you before the Court, rather than before
VA, then you can get information on how to do so by writing directly to the
Court. Upon request, the Court will provide you with a state-by-state
listing of persons admitted to practice before the Court who have indicated
their availability to represent appellants. This information is also
provided on the Court's website at www.vetapp.uscourts.gov.
Do I have to pay an attorney or agent to represent me? Except for a claim
involving a home or small business VA loan under Chapter 37 of title 38,
United States Code, attorneys or agents cannot charge you a fee or accept
payment for services they provide before the date BVA makes a final
decision on your appeal. If you hire an attorney or accredited agent within
1 year of a final BVA decision, then the attorney or agent is allowed to
charge you a fee for representing you before VA in most situations. An
attorney can also charge you for representing you before the Court. VA
cannot pay fees of attorneys or agents.
Fee for VA home and small business loan cases: An attorney or agent may
charge you a reasonable fee for services involving a VA home loan or small
business loan. For more information, read section 5904, title 38, United
States Code.
In all cases, a copy of any fee agreement between you and an attorney or
accredited agent must be sent to:
Office of the Senior Deputy Vice Chairman (012)
Board of Veterans' Appeals
810 Vermont Avenue, NW
Washington, DC 20420
The Board may decide, on its own, to review a fee agreement for
reasonableness, or you or your attorney or agent can file a motion asking
the Board to do so. Send such a motion to the address above for the Office
of the Senior Deputy Vice Chairman at the Board.
VA
FORM
JUN
2003
(RS)
4597
Page
2 |
Corruption is high in Bali, as the cops are underpaid, and the police authorities are just waiting for you to break a rule to charge exorbitant fines. So the best way out is to stay away from getting in their wrong books at all and if you do... |
Q:
jQuery-UI automatically submits its form
When I click a <button>, automatically a (GET-)submit event is triggered. How can I turn this behaviour off?
A:
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Tag Archives: movie review
I just finished watching ‘Up In The Air’. It is an exquisite movie. Great theme!! Great direction and great acting. It is really really good. Too bad I saw it so late in the day.
—Spoiler Alert—
The whole theme is about companionship. Clooney plays a man who has always been against carrying the baggage of any kind of a relationship – blood or otherwise. Eventually he meets someone who he feels he can discard his philosophy for. And then there is a twist. He goes from feeling the bliss of solitude and independence to feeling the need for companionship and the joy it brings. He is disappointed in his new quest and ends up like before – alone and up in the air, travelling light!
—
There is a scene in the movie where he earns 10 million miles and is made to meet a distinguished pilot. It is a moment he has dreamed about all his life. That is what he has been working towards always. He has been imagining it and practicing the conversations he would be having. All of it does not matter when the moment finally arrives. He can’t remember what he had prepared to say. He can’t feel the joy he anticipated. He can’t feel the excitement he thought he would because at that time his priority is something else. It is a powerful scene. Makes one realize that when the moment arrives, it may not at all be like we imagine it would be. Things which matter so much to us at this moment may not be worth it at the next moment. There is always something bigger – a connection which we all need.
The emotions in the movie are controlled and moderated like grown ups do. Excellent watch! Made my night!
..blew me away!! Every aspect of it. Each little and small thing. Kudos and thanks to the people who made it.
First off, the script is incredible. The plot, the story line, the themes, the ideologies , the way they have compared and contrasted people and ideas, it is all just too fantastic. Now, laying a creamy layer on the top of such a juicy base was the hands down award winning performances. Of course I do not need to tell you that Heath Ledger as Joker has outdone every villian in the history of film making. He has given a performance which is a landmark in acting. I can go on gushing about it forever and ever. I cannot even imagine that if he had not done it, how the character would have turned out. He has given so much credibility and truthfulness and authenticity to the character, that not for once did I think that someone was playing it. I believed in the Joker. Christian Bale off course is great as Batman but the movie was not about Batman. It was about so much more. It was as much about the Joker and the white knight, Aaron Carter, as about Batman. And I liked Maggie Gyllenhaal better that Katie Holmes in the character of Rachael Dawes.
When I had seen the first part, Batman Returns, I was hooked. I was sucked into the Batman series. Doing an analysis on it for a course only accentuated the interest, but “The Dark Knight”- it has taken the interest to whole another level. I am now officially a big big fan. What Christopher Nolan and the team has given to us is much much more than a wonderful film. They have shown us a new frontier of entertainment, a possibility of how well a thing could be done. The Dark Knight is superlative. It is transcendental. It has set new standards for superhero movies now.
I am eagerly awaiting the next installment but I know it is going to be long.
Welcome to Sajjanpur could as well be called a Welcome to Quality entertainment. Clean and rich. This is what a movie should be made like. It says all the important things that it wants to say and more. It says that a simple narrative can work wonders in the hands of an able director. Because a director can reap all the benefits from the good actors. The performances are excellent and from each of the cast members. Never once you are left wanting more in the acting department. Shreyas Talpade shines, as does Amrita Rao. She is completely believable as the village belle in her body language, looks and the confused, shy character that she portrays. Ila Arun as the loud superstitious mother is spot on. Awfully good. The actor who played Munnibai needs a special complement. His work was amazing. Ravi Kishan and Rajeshwari do great justice to their short parts. Yashpal Sharma is always good.
As for the themes of the movie, there are many. Right from politics to love to widow remarriage to superstition to plight of immigrant workers to casual village woes and entertainment. It is an all encompassing and all entertaining film. Screenplay is very good which is rare phenomena in Hindi movies but an excellent team produces excellent results. I was shocked to see the fate of Shobharani and Compounder but I am afraid that is totally believable. It still does happen. And the marrying to dog to lift a curse. Absolutely true.
I can’t just put out enough praise. It is not a masterpiece and one should not expect it to be so. But what makes this movie so special to me is the sincerity that is shown in the making of it. That dedication and love and care and nurture shows on the screen.
Shreyas Talpade is such a great actor. Directors should use him more and better. Benegal sir, you should make more movies. Amrita Rao should be given more chances.
So last night after like 3 months I was on movie spree due to some light headedness and reduction of guilt plus I has some free time. So, I downloaded 4 movies from someone who has a complete repertoire of top 250 Imdb movies. The 4 which I took were: One Flew Over the Cuckoo’s Nest, Magnolia, 3:10 to Yuma and For a Few Dollars More.
I started with One Flew Over Cuckoo’s Nest because the novel is so famous and so is the movie plus there was Anthony Hopkins. But 5 minutes into the movie and I realized that Salman Khan’s Kyonki had spoiled this movie for me forever because I has watched Kyonki which is a complete ripoff of One Flew….. So there! I could not take it further because I was agonized once again by the Bollywood Plagiarism. In fact, I think that we should coin a new term for it Blagiarism.
So, then I went to 3:10 to Yuma. It’s a western style but not only violence and bullets and gore. There is much much more to the movie. There is sensibility in there, there is emotion and off course, being a western it is all topped with the Cowboy action and style. Russel Crowe features as Ben Wade, a famous outlaw and extremely good in his trade and guess what!! Crowe kicks ass!!! He is so bloody charming and convincing that you believe in him and you tend to forgive him for being so cruel otherwise. His gun is called the Hand of God. The movie also has Christian Bale, who is an impoverished rancher, trying to save his family and feed them and gets to escort Crowe to the prison train for a reward. Now, that reward is monetary off course but holds much more significance than that. That is what the movie is about. Bale is another tremendous actor. No need to say that he plays his part well. The chemistry that Crowe and Bale generate is phenomenal. One can easily see that brilliance is happening onscreen.
Personally, Russel Crowe blows me off every time I see his performance. He is one of the best actors we have in Hollywood and world wide. Hats off!!
After I witnessed this fine movie, my appetite craved for more, so I then started Magnolia. Magnolia is an assortment of different characters and their lives who somehow are all related in some or the other way. The concept of the movie is that weird things and coincidences which seem like divine providences do happen. The film can boast of a number of major actors and all the central characters are awfully good. Each performance is a gem in itself. There is Julian Moore who never fails to impress me. She is so good looking and plus such a bright actress. Simply brilliant. Tom Cruise, who plays a sex god who gives seminars on Sex is mindblowing. His interview with a reporter is like a knockout punch. He just blowed me over. Amazing performance. In his aggressiveness there is a desperation and anger and his past. I just loved him. Then there is another gem of an actor : Philip Seymour Hoffman. He plays a male nurse and what can I say about his acting. Nothing less than exemplary. Yet another of the finest actors we have the privilege of seeing in our day and age. Magnificent. Other characters are all equally brilliant. That is why the movie despite being a little incoherent manages to be riveting.
Yesterday I watched this much talked about movie “Kung Fu Panda” from the DREAMWORKS house. The central character is a panda who makes his dream come true of becoming a Dragon Warrior. How he does it is the whole film.
Now what works for the movie is the characterization of Po, the Panda, who is fat, big, clumsy, a dreamer and totally adorable. Another thing is the comic timing and the element of lightness that ensues seemingly tense moments. I had a hearty laugh at quite a few instances. A very feel good movie and that makes it a good timepass. There are lessons too there like persistence, believing in self and that there is no secret ingredient to create success. In fact that is the main message of the movie that success comes not from some special gift or formula but because of desire, persistence and belief in the self.
So, I liked the movie. Animation was good. Kungfu principles also were presented in the glorified but acceptable ways. Rating is 4/5.
So, I had heard a lot of positive ravings about this movie and I thought well, Imran Khan looks cute, Genelia is saucy so yeah I can give it a try. And try I did. And, well, the movie was OK. It did not generate anything in me as in no bad or good feeling. I sort of had a very indifferent outlook towards it. The story was utterly cliched but I knew that beforehand. Acting was alright. Imran is promising. Genelia too but sometimes her south Indian pronunciations become a little pronounced which is very fine. I am just saying that it catches your attention unnecessarily. Smita Patil’s son ( I forget his name) was good too. I hope he will go far carrying the legacy of two such great actors.
Everything was so-so. There were some fun and smile moments but they came rather irregularly and the worst thing was the airport scene. Because of these foolish, highly sentimental airport scenes where the girl is going, boy is running, gets caught somewhere but manages to reach even after about 20 incompetent guards try to stop him and then there is the benevolent head of police who believes in young love. Dear devil, it was too much to handle. I am sorry but thats not done and that too in an Aamir influenced film. Ending was sad and so was Genelia’s haircut. She looked ridiculous.
Anyway, not as nice as i expected and hoped it would be. A total timepass. That’s my verdict. What’s yours?
Well, I read the adventures of Tom Sawyer again and relived his childhood with same fascination as I had done many years ago.
I also read Kane and Abel, which is based on some biblical characters Cain and Abel which I don’t know about much but in itself the book was thrilling and kept me interested for a long while before becoming a little burdening towards the end. Other than that, good story telling. Power hungry industrialists, their successes , their tragedies , their struggles and eventual victory make for a good story. I liked it okay!
After that I have started “A Room with a view” by E.M. Forster and somehow, I am finding it very tedious right now to wallow in the victorian age and their typical English antics. So, I have kept the book on hold for a while. I hope i will soon be able to return to it.
So, after dropping the above said book, I leapt on to some management and motivational books because they were the only ones that I had. One is “Born to Win” by Promod Batra and another called “How to get what you want to get” by Havermeyer. Well, about them all I can say is that these books suddenly lift your mood up and light that flame of enthusiasm again whenever you are able to spot a needed statement in them. But what I find most irritating about such books is the inconsistency in the preachings. There are many contradictions which reduce the book from a serious full hearted attempt to just a compiled fact book.
About movies:
Saw Kismat Konnection. Well, wasn’t able to make any connection with the movie. Shahid was good. I went with an open mind and a possible positive bias towards Vidya Balan but she disappointed me again. She does not come across as a light hearted character ever. That irks me. Sometimes the script demands heaviness but not always man! That becomes boring.
Saw Aamir. Loved it! Good attempt. More such movies should be made and fine acting by Rajeev khandelwal. |
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The prices stated may have increased since the last update. Unfortunately it is not possible for us to update the prices on our website in real-time. Should a shop not offer prices in your local currency, we may calculate the displayed price on daily updated exchange rates. |
Q:
WPF ensure transformed content is visible
Does WPF provide a control that automatically transforms contained content to be visible?
I can compute things manually, but I'd rather work with existing Dependency Properties.
I'd like to add content to this hypothetical control, rotate the content, and have the parent perform additional transformation to make sure the entire content is visible.
(Similar to Smallest possible bounding box for a rotated image)
A:
Put the whole content into a Viewbox.
|
North Western Fells
The North Western Fells are a group of hills in the English Lake District. Including such favourites as Catbells and Grisedale Pike, they occupy an oval area beneath the Buttermere and Borrowdale valley systems. The North Western Fells are characterised by soaring east-west ridges and an absence of mountain tarns.
Partition of the Lakeland Fells
The Lake District is a National Park in the north west of the country which, in addition to its lakes, contains a complex range of hills. These are known locally as fells and range from low hills to the highest ground in England. Hundreds of tops exist and many writers have attempted to draw up definitive lists. In doing so the compilers frequently divide the range into smaller areas to aid their description.
The most influential of all such authors was Alfred Wainwright whose Pictorial Guide to the Lakeland Fells series has sold in excess of 2 million copies, being in print continuously since the first volume was published in 1952. Wainwright divided the fells into seven geographical areas, each surrounded by valleys and low passes. While any such division must be arbitrary- and later writers have deviated to a greater or lesser extent from this blueprint- Wainwright's sevenfold division remains the best known partitioning of the fells into 'sub ranges', each with its own characteristics. The North Western Fells are one of these divisions, covered by volume 6 of Wainwright's work.
Boundaries
The North Western Fells form a self-contained unit, its borders being well defined. The only link with other high ground is at the summit of Honister Pass in the extreme south. Across the depression are Fleetwith Pike and the Western Fells. The streams falling east and west from Honister turn gradually northward and flow along roughly parallel courses for around 12 miles. On the west is the River Cocker and its headwaters, passing through the lakes of Buttermere and Crummock Water. The eastern boundary is formed by the Derwent system, including Derwent Water and Bassenthwaite Lake. The Derwent ultimately turns westward and is joined by the Cocker at the town of Cockermouth, completing the circuit.
Topography
Unusually for areas of high fell, the North Western Fells are traversed by two roads. Both cross east to west, connecting the bordering valleys. Newlands Pass runs from Braithwaite village to Buttermere while Whinlatter Pass takes a more northerly route from Braithwaite to High Lorton. These passes divide the North Western Fells into three sectors.
The most southerly sector consists of a ridge running broadly north east to south west. Beginning with the family favourite of Catbells, the high ground continues over Maiden Moor, High Spy, Dale Head, Hindscarth and Robinson. An outlier of High Spy in the 'Jaws of Borrowdale', Castle Crag is listed as a separate fell by Wainwright.
The central area is based around two parallel east-west ridges. The southerly line begins above Derwent Water with the knobbly outline of Causey Pike and then marches west over Scar Crags, Sail, Eel Crag, Wandope and finally Grasmoor. This is the highest of the North Western Fells at 2,795 ft, standing above a dramatic fall to Crummock Water. Outliers to the south of this ridge are Ard Crags, Knott Rigg, Whiteless Pike and Rannerdale Knotts, while Barrow and Outerside stand to the north. The parallel northern ridge includes Grisedale Pike, visible as a fine triangular pyramid from Keswick, Hopegill Head and Whiteside.
The fells to the north of Whinlatter are generally lower and less rugged. They include Whinlatter, Graystones, Broom Fell, Lord's Seat, Barf (with its famous 'Bishop'), Sale Fell and Ling Fell.
Access for walkers
The North Western Fells are entirely surrounded by roads, and additionally traversed by two more. Keswick and Buttermere provide good bases to the north and west while the summits of Honister, Newlands and Whinlatter passes all provide parking. The most popular climb in the area is Cat Bells via Hause End, a walk which can be made from Keswick via the Derwentwater launches.
See also
Eastern Fells
Far Eastern Fells
Central Fells
Southern Fells
Northern Fells
Western Fells
References
Category:Fells of the Lake District |
Recommendations for the assessment and optimization of adherence to disease-modifying drugs in chronic inflammatory rheumatic diseases: A process based on literature reviews and expert consensus.
Adherence to treatment is a key issue in chronic inflammatory rheumatic diseases (CIRDs). To develop recommendations to facilitate in daily practice, the management of non-adherence to disease-modifying drugs in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, connective tissue diseases or other CIRDs. The process comprised (a) systematic literature reviews of methods (including questionnaires) to measure non-adherence, risk factors for non-adherence and efficacy of targeted interventions; (b) development of recommendations through consensus of 104 rheumatologist and nurse experts; (c) assessment of agreement and ease of applicability (1-5 where 5 is highest) by the 104 experts. (a) Overall, 274 publications were analysed. (b) The consensus process led to 5 overarching principles and 10 recommendations regarding adherence. Key points include that adherence should be assessed at each outpatient visit, at least using an open question; questionnaires and hydroxychloroquine blood level assessments may also be useful. Risk factors associated to non-adherence were listed. Patient information and education, and patient/physician shared decision, are key to optimize adherence. Other techniques such as formalized education sessions, motivational interviewing and cognitive behavioral therapy may be useful. All health professionals can get involved and e-health may be a support. (c) The agreement with the recommendations was high (range of means, 3.9-4.5) but ease of applicability was lower (2.7-4.4). Using an evidence-based approach followed by expert consensus, this initiative should improve the assessment and optimization of adherence in chronic inflammatory rheumatic disorders. |
The invention concerns tools for turning, and especially tools for fashioning deep and/or hollow work in materials such as wood, plastics, soft metals and alabaster.
In recent years there has been a resurgence of interest in the art and craft of wood turning, including a particular interest in producing larger vessels of both the "deep" and "hollow" types. Usually the term deep refers to a cavity the internal diameter of which decreases progressively from the mouth to the bottom of the cavity. A simple example is an open cone. The term hollow refers to vessels in which there is at least one internal chamber with a mouth or entrance of smaller diameter than the maximum internal diameter of the chamber. A simple example is a sphere with a circular opening.
Two of the problems facing the turner desiring to fashion deep or hollow vessels significantly larger than those feasible and economical with conventional tools, are the volumes of material to be removed and the much greater reach of tool required. Typically these attempts at larger vessels have been made using somewhat makeshift adaptations of conventional methods and tools. The conventional way of removing redundant material is by comminution (reducing all of the material to shavings or sawdust) for example with a gouge tool. The rough forming of an extra large vessel in this way can be very laborious, time consuming and wasteful of the raw material. (Doubling the principal dimensions of a vessel increases its volume and hence the volume of material to be worked eight times.)
The second problem is the control of tools at the greater reaches involved in fashioning the inside of larger vessels. With the cutting edges of the tool more remote from the tool rest it becomes more difficult to control the tool for accurate work. A simple lengthening of the tool handle may help in holding the tool against the greater leverage resulting from increased tool reach. But typically no provision is made for holding the tool against the increased torsion forces experienced at the tool handle, especially when an offset tool is used.
A conventional tool such as a round nosed scraper may be used in a "slicing" operation to remove some volume of material, as for example in removing a cone from the end of a workpiece at the beginning of fashioning the internal form of a vessel. But the width of such tools (typically about one inch wide) wastes much material in the cuts and the operation is time consuming and inefficient.
With conventional tools, usable reach beyond the tool rest is typically of the order of two to three inches. With some adaptation greater reaches are possible, but usually only in a fatiguing operation without satisfactory control or efficiency. |
This invention relates to armored vests, more particularly, a cover for a ballistics vest pad that permits a user to quickly and easily view the ballistics vest pad.
Currently, armored vests, which are also referred to as bullet-proof vests, comprise three main components: a ballistics vest pad having body-face side and an opposing strike-face side, a non-removable cover (which is also referred to as a pad cover) and a carrier. The ballistics vest pad is encased within the pad cover. A label is placed on the cover of one side of the pad, either the strike-side or the body-side, so as to indicate to the wearer how to insert the pad. When a person desires to use the armored vest, he or she inserts the covered ballistics vest pad into the carrier such that the body-face side of the ballistics cover is against the body and, depending on the type of armored vest, is worn underneath or over the person's clothing.
Oftentimes, however, problems may occur wherein a person, due to carelessness, does not read the label on the cover and inadvertently places the ballistics vest pad into the carrier wherein the body-face portion is not facing the body. As the ballistics vest pad is designed wherein the strike-face side is able to withstand the impact of a bullet greater than the body-face side, this mistake could cost the wearer his or her life.
In addition, the ballistics vest pad of the armored vest is normally warranted for only five years. However, as the condition of the armored vest is determined by the amount of use, five years is a only a general guideline. For example, if an armored vest is receiving considerable use, then the condition of the armored vest is greatly diminished well before five years whereas an armored vest that is rarely used may have a life-span well over five years. In addition, if the ballistics vest pad gets wet with sweat, water or other liquid, there is a great likelihood that the ballistics vest pad will become moldy. Also, some fabrics used to make ballistics delaminate with use. Thus, it is important for the wearer of the armored vest to know the condition of the ballistics vest pad prior to wearing the vest.
However, because the cover is opaque, the condition of the ballistics vest pad is not readily apparent. In addition, because the cover is non-removable, a person must rip open the cover to view the condition of the ballistics vest pad and, once the cover is ripped, the entire ballistics system is destroyed, requiring the purchase of a new covered ballistics vest pad. Thus, the users of armored vests rarely, if ever, check the condition of the ballistics vest pad of an armored vest as it is not convenient to do so. Unfortunately, if a person uses a ballistics vest pad that has been compromised, he or she is placing his or her life in danger wherein the potential consequence is death.
Thus, a need exists for a ballistics vest pad cover that permits a person to quickly and easily view the condition of the ballistics vest pad without damaging the covered ballistics vest pad.
The relevant prior art includes the following references:
U.S. Pat. No.(U.S. unless stated otherwise)InventorIssue/Publication Date5,127,105SacksJul. 07, 19925,471,906Bachner, Jr. et al.Dec. 05, 19955,063,614McShefferyNov. 12, 19916,704,934Graham et al.Mar. 16, 20044,510,200SamowichApr. 09, 19852005/0193459Field et al.Sep. 08, 20056,845,513Field et al.Jan. 25, 20056,526,862LyonsMar. 04, 20034,413,357SacksNov. 08, 19834,198,707Haupt et al.Apr. 22, 19803,398,406WaterburyAug. 27, 1968 |
Fis1, DLP1, and Pex11p coordinately regulate peroxisome morphogenesis.
Dynamin-like protein 1 (DLP1) and Pex11pbeta function in morphogenesis of peroxisomes. In the present work, we investigated whether Fis1 is involved in fission of peroxisomes. Endogenous Fis1 was morphologically detected in peroxisomes as well as mitochondria in wild-type CHO-K1 and DLP1-defective ZP121 cells. Subcellular fractionation studies also revealed the presence of Fis1 in peroxisomes. Peroxisomal Fis1 showed the same topology, i.e., C-tail anchored membrane protein, as the mitochondrial one. Furthermore, ectopic expression of FIS1 induced peroxisome proliferation in CHO-K1 cells, while the interference of FIS1 RNA resulted in tubulation of peroxisomes, hence reducing the number of peroxisomes. Fis1 interacted with Pex11pbeta, by direct binding apparently involving the C-terminal region of Pex11pbeta in the interaction. Pex11pbeta also interacted with each other, whereas the binding of Pex11pbeta to DLP1 was not detectable. Moreover, ternary complexes comprising Fis1, Pex11pbeta, and DLP1 were detected by chemical cross-linking. We also showed that the highly conserved N-terminal domain of Pex11pbeta was required for the homo-oligomerization of Pex11pbeta and indispensable for the peroxisome-proliferating activity. Taken together, these findings indicate that Fis1 plays important roles in peroxisome division and maintenance of peroxisome morphology in mammalian cells, possibly in a concerted manner with Pex11pbeta and DLP1. |
Hotels in Edinburgh
Georgian streets, the world’s largest arts festival, a 12th century castle... Edinburgh has more history and culture than you can fling a bit of shortbread at. So we’ve created this Edinburgh local guide to help you navigate your way around. Surrounded by stunning scenery, its natural good looks make it easy on the eye, but stop gawping for long enough and you’ll find a fabulously independent eating and nightlife scene, too. On a family break in Edinburgh? With both a zoo and a National museum, there’s plenty to keep the little ones occupied. But no matter what you decide to do, rest assured there’s a Premier Inn hotel nearby, ready to get your city break off to the best possible start.
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What to do in Edinburgh
Walk the Royal MileFrom Edinburgh Castle to the Palace of Holyroodhouse via the Scottish Parliament Building, walking Edinburgh’s Royal Mile end to end is a whistle-stop tour of Scottish history.
The Real Mary King’s CloseUnderneath the Royal Mile lies The Real Mary King’s Close - a fascinating subterranean network of medieval alleys. Find out from Mary King what life here was like in the 17th-century.
The Scottish Storytelling CentreEnjoy an all-round programme of theatre, exhibitions, music, family activities and festivals such as TradFest and the Scottish International Storytelling Festival.
Edinburgh DungeonWith the help of seasoned actors, this 80-minute experience delves into the bloody, gruesome and ghostly side of Scotland’s past. Robust constitution preferable.
Camera ObscuraTest your eyesight with five floors of optical illusions and mind-bending wonkiness that have been simultaneously confusing and amazing people since 1853. You quite literally won’t believe your eyes.
The Scotch Whisky ExperienceFind out how Scotland’s finest export is made, and check out the world’s largest selection of Scotch. Adults get to sample a wee dram, and kids can binge on Irn Bru. If you’re staying at one of our Edinburgh business hotels, better save this one until after work.
Burns NightTributes to Scotland’s National Bard, Robert Burns, are held on his birthday – the 25th January – every year. Join a Burns Supper, attend a ceilidh or simply raise a toast with a dram or two of whisky.
Edinburgh Festival FringeThe Fringe attracts fantastic performers and enthusiastic audiences from all around the world. The programme is released every spring – but book your hotel well in advance.
Edinburgh International Film FestivalCatch documentaries, dramas and more by the most promising new talent in international cinema at the world’s longest film festival, spanning twelve days at the end of every June.
Getting aroundWith an international airport five miles west of the city centre and two major train stations, you won’t have any problems getting to Edinburgh. But how should you travel once you get here? Our guide has all the answers.
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Airport parking
Airport parking is hassle-free when you book through our partners at Holiday Extras. Add airport parking after your hotel booking and wake up ready to enjoy your flight, with your car parking completely taken care of.
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Airport lounges
Start your trip in VIP style and enjoy comfy seats, internet access, complimentary food & drink and more at an airport lounge before you take off. Add an airport lounge after your hotel booking easily with our partners, Holiday Extras.
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Fast track
Zoom through passport control and security with a fast track pass. Add a fast track pass after your hotel booking with our partner, Holiday Extras, and you’ll move to the priority lane – spend less time queuing and more time relaxing before your flight.
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Influence of the new premix with iodine content on the quantitative indices of iodine accumulation in egg.
In order to increase the assortment of food products, enriched with iodine natural compound, we decided to study the influence of the new premix with iodine content on the quantitative indices of iodine accumulation in eggs. The iodized premix was prepared on the spot by A.Kalandarishvili's method. The experiments were conducted on 140-250 days old Cross Loman-Classic layer hens. The iodine quantitative determination was conducted by the kinetic method. We used the bran premix with iodine content, in which optimum concentration of iodine fluctuated from 500 up to 1000 mkg, as food additive for the feeding of laying hens taking into account the best hematological indices. The correlation between the iodine quantity in egg, iodine concentration in premix and the intensity of egg lying has been determined. |
@comment $NetBSD: PLIST,v 1.1 2016/02/08 05:48:07 agc Exp $
include/cre2.h
info/cre2.info
lib/libcre2.la
share/doc/cre2/COPYING
share/doc/cre2/LICENSE.re2
share/doc/cre2/README
|
SWOT Analysis
We’re Headed for a Golden Cross
Every week, our investment team reviews a variety of sources to formulate a summary of the top events in the gold, resources, and emerging markets. The results are categorized in terms of strengths, weaknesses, opportunities and threats. We believe this SWOT model helps investors make informed decisions about their gold and gold stock investments.
For the week beginning March 10, here is the SWOT for the gold market.
Strengths
Gold posted a very strong week, rising $43.07 per ounce as Chinese macroeconomic data revived fears of a global slowdown, and geopolitical tensions brewed ahead of the scheduled Crimea referendum this weekend. Furthermore,
as shown on the chart above, the 50-day moving average closed less than $10 below the 200-day moving average, which implies that barring a gold collapse below $1,300 next week, we should see gold making a golden cross before the end of the week. Our analysis shows that, going back to 2000, a golden cross in gold is followed on average by a 50 percent rally lasting on average 15 months.
Gold ETFs appear to be back in fashion, as total known gold ETF holdings are now 870 thousand ounces higher since bottoming at 55.8 million ounces in mid-February. The ETF data comes as the situation in Ukraine reinforces gold’s safe haven status and the weak macroeconomic data coming from China highlight gold’s hedging properties amid a risk-off investing environment.
Pretium Resources announced the addition of James Currie to its executive team as chief operating officer. Currie has notable mine-building experience, and was recently chief operating officer for New Gold where he led the construction of the New Afton gold mine. On a different note, Aldridge Minerals received environmental approval for its Yenipazar Project in central Turkey. With the completion of this milestone, Aldridge is positioned to advance the project towards financing and construction.
Weaknesses
The China Gold Association (CGA) said China’s gold demand may decline by 17 percent to 250 tonnes in the first quarter of 2014, from 300 tonnes in the first quarter of 2013. Despite this fact, CGA vice chairman Zhang Yongtao expects annual demand to remain strong at 1,176 tonnes, very close to the actual annual demand for 2013. According to HSBC Research, Mr. Zhang's forecast indicates that China's gold demand should be stronger for the rest of 2014 after the first quarter, when compared to the same period in 2013. This may indicate that China's strong appetite for gold is likely to be sustained well into 2014.
As part of its fourth-quarter results release, Detour Gold stated it is permitted to enter into transactions to hedge up to 50 percent of its forecasted gold sales. As a result, Detour sold forward 40 thousand ounces at $1,241 and 45 thousand ounces at $1,327, for a total of 85 thousand ounces at $1,287. With gold closing above $1,380 per ounce today, it could be said that the hedging exercise will cost Detour shareholders nearly $80 million in forgone revenue this year.
Hochschild Mining suspended its full-year dividend despite beating its production guidance. According to the company’s top management, 2013 proved to be a very challenging year, and despite the cost saving and cash flow optimization measures implemented, the company posted a net loss of $128.7 million after impairments, and decided to suspend its payout.
Opportunities
A Royal Bank of Canada report shows similarities between the 2005 to 2008 gold price rally and the current gold price environment, which analysts believe could lead to a sustained gold price rally over the next 12 to 24 months. While still early in gold recovering from its lows, Chinese and emerging market gold demand combined with the absence of central bank selling both offset any ETF liquidations. Given the volumes seen in China recently, and the fact the Chinese market is not as price sensitive – thanks to high savings rates – Chinese demand on its own could replicate the 2005-08 ETF-driven gold rally.
Integra Gold Corp. reported the results of the preliminary economic assessment carried out at its flagship Lamaque Gold project in Val d’Or, Quebec, showing an expected after-tax internal rate of return of 38 percent on peak annual production of 143,000 ounces per year. The Lamaque project is one of a handful of high grade, low capex, and stable jurisdiction projects in development right now. On a similar note, Alacer Gold reported record annual gold production at its Copler gold mine, at all-in costs of $864 per ounce. The company expects this outstanding performance to continue into 2014, at one of the lowest all-in costs in the industry.
An independent analysis has determined that Australia’s Mineral Resource Rent Tax (MRRT) has only managed to raise A$232 million this fiscal year, a far cry from the A$4 billion originally forecast. A spokeswoman for Australia’s Treasurer Joe Hockey stated the tax should be eliminated because it has destroyed jobs and investment. Australia’s Prime Minister Tony Abbott has pledged to repeal the tax.
Threats
A recent report by several non-governmental organizations including the Sierra Club asserts NAFTA “provided the ingredients for an explosion of dangerous foreign mining activity in Mexico.” Dorothy Kosich, Americas’ Editor for Mineweb, reports contents of the original report stating Mexico has become the largest importer of multiple toxic chemicals which are major sources of water contamination. The report concludes that NAFTA has protected foreign mining corporations and allowed harmful environmental impacts to Mexico.
A wave of weak economic data released by the Chinese government agencies this week helped propel gold higher as U.S. and Europe markets weighed the risk of a deceleration in Chinese economic growth. The weak data points released show the risk of Chinese physical gold and jewelry buyers to defer consumption to a later date. As a matter of fact, Chinese retail sales data showed growth of 11.8 percent, missing analysts’ estimates for a 13.5 percent increase. As a result, gold demand from China may be lower in the short term, or until the festive and marriage season starts later in the year.
The instability in Ukraine, together with the China hard-landing fears, has not changed Goldman Sachs’ bearish view on gold. According to Jeffrey Currie, the bank’s head of commodities research, the weakness in the U.S. and the turmoil in Ukraine are not driving gold. Instead, the lower mining costs mean it is more probable that gold drops below $1,000. Marc Faber on the other hand believes the near tripling of the S&P 500 since the end of the bear market in 2009, together with heavy insider selling, high valuations, and extremely high corporate profits should make any investor consider the possibility that we may be at a top of the U.S. equity cycle.
See the strengths, weaknesses, opportunities and threats of the gold, resources and emerging markets every week by subscribing to the Investor Alert. It arrives in your email inbox every Friday evening and best yet, it’s free.
All opinions expressed and data provided are subject to change without notice. Some of these opinions may not be appropriate to every investor. Past performance does not guarantee future results. The following securities mentioned were held by one or more of U.S. Global Investors Funds as of 12/31/13: Alacer Gold Corp, Aldridge Minerals Inc., New Gold Inc., Pretium Resources Inc. |
Home quarantines are never fun, but a good beer can make it better.
That's what the folks at Eastern Market Brewing Co. believe. In the wake of Gov. Gretchen Whitmer's executive order to close bars and in-person dining beginning 3 p.m. Monday, the craft brewer is launching a beer delivery service.
Delivery of beer to homes is allowed under Michigan law, and for small brewers, it could mean the difference between staying afloat and closing permanently.
"The timing couldn't be worse for our industry," Dayne Bartscht, co-owner of Detroit-based Eastern Market Brewing, told Crain's on Monday. "January and February, we take a loss. March is when we start digging out of it. For this to come in March when we are finally starting to see some light is horrible."
Bartscht said the brewery will begin beer delivery this weekend out of its new Ferndale operation, offering it initially to addresses within the Oakland County city. He said by the end of the month, he aims to have the service available to nearby cities, including Detroit, and eventually throughout Southeast Michigan.
Bartscht said he's in talks with a few technology companies to launch a delivery app called Wing It. If the app isn't running by this weekend, orders can be made online. The brewery is also exploring food delivery.
Around 20 of the company's 48 employees will be making deliveries with their personal vehicles. Several precautions will be taken — cans will be sanitized, all transactions will happen digitally and delivery drivers won't come within 6 feet of recipients, Bartscht said.
The brewery's two locations will still offer carryout beer sales.
"I've had a lot of sleepless nights thinking about what we would do with our employees if there was gonna be a full shutdown," Bartscht said. "Really, that was the impetus of bringing this to market quickly." |
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(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>executeQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a68ad8597e3e9f709937c5d242e7be6cf"></a><!-- doxytag: member="FMDatabase::executeQueryWithFormat:" ref="a68ad8597e3e9f709937c5d242e7be6cf" args="(NSString *format,[,]...)" -->
(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>executeQueryWithFormat:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a9d4d6047ba52d46b7ad0788121c7062e"></a><!-- doxytag: member="FMDatabase::executeQuery:withArgumentsInArray:" ref="a9d4d6047ba52d46b7ad0788121c7062e" args="(NSString *sql,[withArgumentsInArray] NSArray *arguments)" -->
(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>executeQuery:withArgumentsInArray:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a598f5b286bfc5348e3f9b43c1322b854"></a><!-- doxytag: member="FMDatabase::executeQuery:withArgumentsInArray:orVAList:" ref="a598f5b286bfc5348e3f9b43c1322b854" args="(NSString *sql,[withArgumentsInArray] NSArray *arrayArgs,[orVAList] va_list args)" -->
(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>executeQuery:withArgumentsInArray:orVAList:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aca57bb48b7b6bd6b72d792aa6aec64d8"></a><!-- doxytag: member="FMDatabase::rollback" ref="aca57bb48b7b6bd6b72d792aa6aec64d8" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>rollback</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a519cd86399c732163b05b0e98e5099c6"></a><!-- doxytag: member="FMDatabase::commit" ref="a519cd86399c732163b05b0e98e5099c6" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>commit</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a33e9a1ee03b77f79325d6dac83338341"></a><!-- doxytag: member="FMDatabase::beginTransaction" ref="a33e9a1ee03b77f79325d6dac83338341" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>beginTransaction</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="afd7dd530bc2b567a364eac1b2e749c89"></a><!-- doxytag: member="FMDatabase::beginDeferredTransaction" ref="afd7dd530bc2b567a364eac1b2e749c89" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>beginDeferredTransaction</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a6f11640d267ede43dded32c21a4c9a87"></a><!-- doxytag: member="FMDatabase::inUse" ref="a6f11640d267ede43dded32c21a4c9a87" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>inUse</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aa348392c5e8dce1af421e3352a7f99a2"></a><!-- doxytag: member="FMDatabase::setInUse:" ref="aa348392c5e8dce1af421e3352a7f99a2" args="(BOOL value)" -->
(void) </td><td class="memItemRight" valign="bottom">- <b>setInUse:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a3a5c40561d0865a30ed78bb18fdad75b"></a><!-- doxytag: member="FMDatabase::shouldCacheStatements" ref="a3a5c40561d0865a30ed78bb18fdad75b" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>shouldCacheStatements</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a70fd622196d2dda705a550da36a091d1"></a><!-- doxytag: member="FMDatabase::setShouldCacheStatements:" ref="a70fd622196d2dda705a550da36a091d1" args="(BOOL value)" -->
(void) </td><td class="memItemRight" valign="bottom">- <b>setShouldCacheStatements:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ae71fc399d0a0d94873042c4c9ce6a63a"></a><!-- doxytag: member="FMDatabase::changes" ref="ae71fc399d0a0d94873042c4c9ce6a63a" args="()" -->
(int) </td><td class="memItemRight" valign="bottom">- <b>changes</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a05461040cfb63a9d03d742fd626765d5"></a><!-- doxytag: member="FMDatabase::resultSetDidClose:" ref="a05461040cfb63a9d03d742fd626765d5" args="(FMResultSet *resultSet)" -->
(void) </td><td class="memItemRight" valign="bottom">- <b>resultSetDidClose:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aa0eb7bd25865eb54f7d77b8035f1fd92"></a><!-- doxytag: member="FMDatabase::intForQuery:" ref="aa0eb7bd25865eb54f7d77b8035f1fd92" args="(NSString *objs,[,]...)" -->
(int) </td><td class="memItemRight" valign="bottom">- <b>intForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ab2ac524e73cea8a609b5dfb489bcb071"></a><!-- doxytag: member="FMDatabase::longForQuery:" ref="ab2ac524e73cea8a609b5dfb489bcb071" args="(NSString *objs,[,]...)" -->
(long) </td><td class="memItemRight" valign="bottom">- <b>longForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aec0fb2e325eaf6ab5f26e6078067b63f"></a><!-- doxytag: member="FMDatabase::boolForQuery:" ref="aec0fb2e325eaf6ab5f26e6078067b63f" args="(NSString *objs,[,]...)" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>boolForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a0b0cc9c375905e7fa87e86e4a509e992"></a><!-- doxytag: member="FMDatabase::doubleForQuery:" ref="a0b0cc9c375905e7fa87e86e4a509e992" args="(NSString *objs,[,]...)" -->
(double) </td><td class="memItemRight" valign="bottom">- <b>doubleForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a346de70f6d49a81b0945e514ff279047"></a><!-- doxytag: member="FMDatabase::stringForQuery:" ref="a346de70f6d49a81b0945e514ff279047" args="(NSString *objs,[,]...)" -->
(NSString *) </td><td class="memItemRight" valign="bottom">- <b>stringForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a2db60df1a30015b67ea5cce064a0abc1"></a><!-- doxytag: member="FMDatabase::dataForQuery:" ref="a2db60df1a30015b67ea5cce064a0abc1" args="(NSString *objs,[,]...)" -->
(NSData *) </td><td class="memItemRight" valign="bottom">- <b>dataForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a19e058249f385cb2acfc6c3c1ea88882"></a><!-- doxytag: member="FMDatabase::dateForQuery:" ref="a19e058249f385cb2acfc6c3c1ea88882" args="(NSString *objs,[,]...)" -->
(NSDate *) </td><td class="memItemRight" valign="bottom">- <b>dateForQuery:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ac091185633fc917833d84c2f8c5497f9"></a><!-- doxytag: member="FMDatabase::tableExists:" ref="ac091185633fc917833d84c2f8c5497f9" args="(NSString *tableName)" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>tableExists:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a3fbe3a54bf011e7d5a9824c441b787fb"></a><!-- doxytag: member="FMDatabase::getSchema" ref="a3fbe3a54bf011e7d5a9824c441b787fb" args="()" -->
(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>getSchema</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aa95f5097d08789d8164bde9526f9ab0e"></a><!-- doxytag: member="FMDatabase::getTableSchema:" ref="aa95f5097d08789d8164bde9526f9ab0e" args="(NSString *tableName)" -->
(<a class="el" href="interface_f_m_result_set.html">FMResultSet</a> *) </td><td class="memItemRight" valign="bottom">- <b>getTableSchema:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a0544b532dc8d6e1958a38de31429bff3"></a><!-- doxytag: member="FMDatabase::columnExists:columnName:" ref="a0544b532dc8d6e1958a38de31429bff3" args="(NSString *tableName,[columnName] NSString *columnName)" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>columnExists:columnName:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="aa4a2008f483377d728fb9dd9bc77cfe1"></a><!-- doxytag: member="FMDatabase::validateSQL:error:" ref="aa4a2008f483377d728fb9dd9bc77cfe1" args="(NSString *sql,[error] NSError **error)" -->
(BOOL) </td><td class="memItemRight" valign="bottom">- <b>validateSQL:error:</b></td></tr>
<tr><td colspan="2"><h2><a name="pub-static-methods"></a>
Static Public Member Functions</h2></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ab65b63dadcef6dfc1b9ad69b5e87121b"></a><!-- doxytag: member="FMDatabase::databaseWithPath:" ref="ab65b63dadcef6dfc1b9ad69b5e87121b" args="(NSString *inPath)" -->
(id) </td><td class="memItemRight" valign="bottom">+ <b>databaseWithPath:</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a532eb7417f941f35a0bc33417e1ecd24"></a><!-- doxytag: member="FMDatabase::isThreadSafe" ref="a532eb7417f941f35a0bc33417e1ecd24" args="()" -->
(BOOL) </td><td class="memItemRight" valign="bottom">+ <b>isThreadSafe</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="af5346854489f87c6842d6cc9e89e3c01"></a><!-- doxytag: member="FMDatabase::sqliteLibVersion" ref="af5346854489f87c6842d6cc9e89e3c01" args="()" -->
(NSString *) </td><td class="memItemRight" valign="bottom">+ <b>sqliteLibVersion</b></td></tr>
<tr><td colspan="2"><h2><a name="pro-attribs"></a>
Protected Attributes</h2></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ad6e663497d2c934364b3bcf07496b30b"></a><!-- doxytag: member="FMDatabase::db" ref="ad6e663497d2c934364b3bcf07496b30b" args="" -->
sqlite3 * </td><td class="memItemRight" valign="bottom"><b>db</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a4bc10b66b56b688687e0b682605e3a8f"></a><!-- doxytag: member="FMDatabase::databasePath" ref="a4bc10b66b56b688687e0b682605e3a8f" args="" -->
NSString * </td><td class="memItemRight" valign="bottom"><b>databasePath</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="abd0d0cf0ca1a54786f383d279a02bdb6"></a><!-- doxytag: member="FMDatabase::inUse" ref="abd0d0cf0ca1a54786f383d279a02bdb6" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>inUse</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a2876c2ced35db47c09e064cb9682ca5c"></a><!-- doxytag: member="FMDatabase::shouldCacheStatements" ref="a2876c2ced35db47c09e064cb9682ca5c" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>shouldCacheStatements</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a397b5283bd12489fe26fb4e2f91d5292"></a><!-- doxytag: member="FMDatabase::openResultSets" ref="a397b5283bd12489fe26fb4e2f91d5292" args="" -->
NSMutableSet * </td><td class="memItemRight" valign="bottom"><b>openResultSets</b></td></tr>
<tr><td colspan="2"><h2><a name="properties"></a>
Properties</h2></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a61ce165c427cfc57efe913775812475b"></a><!-- doxytag: member="FMDatabase::inTransaction" ref="a61ce165c427cfc57efe913775812475b" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>inTransaction</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a4bc183e011ee69f872d5fa0f05cb6945"></a><!-- doxytag: member="FMDatabase::traceExecution" ref="a4bc183e011ee69f872d5fa0f05cb6945" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>traceExecution</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a23edca6316673173c0d94a0496703f8e"></a><!-- doxytag: member="FMDatabase::checkedOut" ref="a23edca6316673173c0d94a0496703f8e" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>checkedOut</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ae891eb83b8fac2fb9686f1f7a93882be"></a><!-- doxytag: member="FMDatabase::busyRetryTimeout" ref="ae891eb83b8fac2fb9686f1f7a93882be" args="" -->
int </td><td class="memItemRight" valign="bottom"><b>busyRetryTimeout</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="a990d4552606048805c0b391daeda8a89"></a><!-- doxytag: member="FMDatabase::crashOnErrors" ref="a990d4552606048805c0b391daeda8a89" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>crashOnErrors</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="af1ceb2fdce07b0dbb0946c85435a562b"></a><!-- doxytag: member="FMDatabase::logsErrors" ref="af1ceb2fdce07b0dbb0946c85435a562b" args="" -->
BOOL </td><td class="memItemRight" valign="bottom"><b>logsErrors</b></td></tr>
<tr><td class="memItemLeft" align="right" valign="top"><a class="anchor" id="ab42d841645a304cc8e6ab26654ecc012"></a><!-- doxytag: member="FMDatabase::cachedStatements" ref="ab42d841645a304cc8e6ab26654ecc012" args="" -->
NSMutableDictionary * </td><td class="memItemRight" valign="bottom"><b>cachedStatements</b></td></tr>
</table>
<hr/><a name="details" id="details"></a><h2>Detailed Description</h2>
<div class="textblock">
<p>Definition at line <a class="el" href="_f_m_database_8h_source.html#l00005">5</a> of file <a class="el" href="_f_m_database_8h_source.html">FMDatabase.h</a>.</p>
</div><hr/>The documentation for this class was generated from the following files:<ul>
<li>Classes/FMDB/<a class="el" href="_f_m_database_8h_source.html">FMDatabase.h</a></li>
<li>Classes/FMDB/<a class="el" href="_f_m_database_8m_source.html">FMDatabase.m</a></li>
</ul>
</div>
</div>
<div id="nav-path" class="navpath">
<ul>
<li class="navelem"><a class="el" href="interface_f_m_database.html">FMDatabase</a> </li>
<li class="footer">Generated on Mon Sep 26 2011 18:50:24 for CommandServiceManager by 
<a href="http://www.doxygen.org/index.html">
<img class="footer" src="doxygen.png" alt="doxygen"/></a> 1.7.4 </li>
</ul>
</div>
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onmouseover="return searchBox.OnSearchSelectShow()"
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onkeydown="return searchBox.OnSearchSelectKey(event)">
<a class="SelectItem" href="javascript:void(0)" onclick="searchBox.OnSelectItem(0)"><span class="SelectionMark"> </span>All</a><a class="SelectItem" href="javascript:void(0)" onclick="searchBox.OnSelectItem(1)"><span class="SelectionMark"> </span>Data Structures</a><a class="SelectItem" href="javascript:void(0)" onclick="searchBox.OnSelectItem(2)"><span class="SelectionMark"> </span>Functions</a><a class="SelectItem" href="javascript:void(0)" onclick="searchBox.OnSelectItem(3)"><span class="SelectionMark"> </span>Properties</a></div>
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|
# -*- coding: utf-8 -*-
#
# GHC Users Guide documentation build configuration file
#
# This file is execfile()d with the current directory set to its
# containing dir.
#
import sys
import os
import sphinx_rtd_theme
# Support for :base-ref:, etc.
sys.path.insert(0, os.path.abspath('.'))
import cabaldomain
version = "3.5.0.0"
extensions = ['sphinx.ext.extlinks', 'sphinx.ext.todo']
templates_path = ['_templates']
source_suffix = '.rst'
source_encoding = 'utf-8-sig'
master_doc = 'index'
# extlinks -- see http://www.sphinx-doc.org/en/stable/ext/extlinks.html
extlinks = {
'issue': ('https://github.com/haskell/cabal/issues/%s', '#'),
'ghc-wiki': ('https://gitlab.haskell.org/ghc/ghc/-/wikis/%s', ''),
'ghc-ticket': ('https://gitlab.haskell.org/ghc/ghc/-/issues/%s', 'GHC #'),
'hackage-pkg': ('http://hackage.haskell.org/package/%s', ''),
}
# General information about the project.
project = u'Cabal'
copyright = u'2003-2020, Cabal Team'
# N.B. version comes from ghc_config
release = version # The full version, including alpha/beta/rc tags.
# Syntax highlighting
highlight_language = 'cabal'
#pygments_style = 'tango'
primary_domain = 'cabal'
# List of patterns, relative to source directory, that match files and
# directories to ignore when looking for source files.
exclude_patterns = ['.build', "*.gen.rst"]
# -- Options for HTML output ---------------------------------------------
# on_rtd is whether we are on readthedocs.org, this line of code grabbed from docs.readthedocs.org
on_rtd = os.environ.get('READTHEDOCS', None) == 'True'
if not on_rtd: # only import and set the theme if we're building docs locally
import sphinx_rtd_theme
html_theme = 'sphinx_rtd_theme'
html_theme_path = [sphinx_rtd_theme.get_html_theme_path()]
# The name for this set of Sphinx documents. If None, it defaults to
# "<project> v<release> documentation".
html_title = "Cabal {} User's Guide".format(release)
html_short_title = "Cabal %s User's Guide" % release
html_logo = 'images/Cabal-dark.png'
html_static_path = ['images']
# Convert quotes and dashes to typographically correct entities
html_use_smartypants = True
html_show_copyright = True
html_context = {
'source_url_prefix': "https://github.com/haskell/cabal/tree/master/doc/",
"display_github": True,
"github_host": "github.com",
"github_user": "haskell",
"github_repo": 'cabal',
"github_version": "master/",
"conf_py_path": "doc/",
"source_suffix": '.rst',
}
# If true, an OpenSearch description file will be output, and all pages will
# contain a <link> tag referring to it. The value of this option must be the
# base URL from which the finished HTML is served.
#html_use_opensearch = ''
# This is the file name suffix for HTML files (e.g. ".xhtml").
#html_file_suffix = None
# Output file base name for HTML help builder.
htmlhelp_basename = 'CabalUsersGuide'
# MathJax to use SVG rendering by default
mathjax_path = 'https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.5/latest.js?config=TeX-AMS-MML_SVG'
# -- Options for LaTeX output ---------------------------------------------
latex_elements = {
'inputenc': '',
'utf8extra': '',
'preamble': r'''
\usepackage{fontspec}
\usepackage{makeidx}
\setsansfont{DejaVu Sans}
\setromanfont{DejaVu Serif}
\setmonofont{DejaVu Sans Mono}
''',
}
# Grouping the document tree into LaTeX files. List of tuples
# (source start file, target name, title,
# author, documentclass [howto, manual, or own class]).
latex_documents = [
('index', 'users_guide.tex', u'GHC Users Guide Documentation',
u'GHC Team', 'manual'),
]
# The name of an image file (relative to this directory) to place at the top of
# the title page.
#latex_logo = 'images/logo.pdf'
latex_logo = 'images/Cabal-dark.png'
# If true, show page references after internal links.
latex_show_pagerefs = True
# http://www.sphinx-doc.org/en/master/usage/extensions/todo.html
todo_include_todos = True
# -- Options for manual page output ---------------------------------------
# One entry per manual page. List of tuples
# (source start file, name, description, authors, manual section).
man_pages = [
('cabal', 'cabal', 'The Haskell Cabal', 'The Cabal Team', 1)
]
# If true, show URL addresses after external links.
#man_show_urls = False
# -- Options for Texinfo output -------------------------------------------
# Grouping the document tree into Texinfo files. List of tuples
# (source start file, target name, title, author,
# dir menu entry, description, category)
texinfo_documents = [
('index', 'CabalUsersGuide', u'Cabal Users Guide',
u'Cabal Team', 'CabalUsersGuide', 'The Haskell Cabal.',
'Compilers'),
]
from sphinx import addnodes
from docutils import nodes
def parse_ghci_cmd(env, sig, signode):
name = sig.split(';')[0]
sig = sig.replace(';', '')
signode += addnodes.desc_name(name, sig)
return name
def parse_flag(env, sig, signode):
import re
names = []
for i, flag in enumerate(sig.split(',')):
flag = flag.strip()
sep = '='
parts = flag.split('=')
if len(parts) == 1:
sep=' '
parts = flag.split()
if len(parts) == 0: continue
name = parts[0]
names.append(name)
sig = sep + ' '.join(parts[1:])
sig = re.sub(r'<([-a-zA-Z ]+)>', r'⟨\1⟩', sig)
if i > 0:
signode += addnodes.desc_name(', ', ', ')
signode += addnodes.desc_name(name, name)
if len(sig) > 0:
signode += addnodes.desc_addname(sig, sig)
return names[0]
def setup(app):
from sphinx.util.docfields import Field, TypedField
increase_python_stack()
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Occasionally we do good here, instead of the usual evil. Case in point: when a young lady met Manhattan Casanova and creepy sexual compulsive Paul Janka at a restaurant recently, she almost fell prey to his inexplicable charms. But she figured out who he was after he had her come to the Upper East Side for drinks, and then refused to come down from his apartment, hoping that she would feel pressured to enter into his lair. (That's his M.O.!) "Your blog basically saved me tonight," she wrote. "Last thursday I was at JG Melons and met this guy who gave me the F*** me eyes..." The story, and text convo, after the jump.
I stupidly gave him my bcard, as he asked me out for drinks. Last night (sat) we had plans and basically he said he was in brooklyn and wouldnt be able to meet me till later. Tried to get me to his apt, but I said I dont go to men's apts. So we made plans to meet tonight and he said to come to his neighborhood. He I said ok and he said 68th and madison.When I got there I called and he said to come up (a la the Dec14th post email you guys put up). I said I already explained I couldnt do that and that he had to come down. He politely texted meback with "Im sorry I cant do that, sorry to have wasted your time." ...I randomly thought it sounded familiar soi googled him and then looked on Gawker..."
2:04PM(Girl) Let me know if you want to do something today/tonight?
2:12PM (Janka) Yes. Around 9? What did you do last night?
2:13PM (Girl) Watched the fugitive and went to sleep. 9 works.
6:01PM (Janka) I will be on 82nd street at 7:30. Ill come say hi.....
6:34PM (Girl) I am going to the gym! Sorry.
6:50PM (Girl) Do you still want to grab a drink at 9?
6:54PM (Janka) Yes. What time are you going to the gym and what time are you returning?
6:57PM (Girl) Im headed there now- should be home around 8:15.
8:23PM (Girl) So what's ur deal?
8:26PM (Janka) Let's meet in 30
8:54PM (Janka) Come here and we'll grab something
8:58pm (Girl) Come where? I need like 15 min got tied up on a con call
8:59PM (Janka) This neck of the woods. Nice night. You can walk it....
9:04PM (Girl) 68th and Madison?
9:004PM (Janka) Sounds good.
9:18PM (Girl) On my way- 10min
9:18PM (Janka) k
9:34PM (Girl) I'm around the corner be there in a sec
9:35PM (Janka) k
9:36PM (Girl) And you'll meet me where by outside MaxMara
9:40PM (Janka) [redacted] East 68th Apt [redacted]
9:40PM (Girl) I'm not coming up I told you that last night.....remember? Meet me downstairs
9:41PM (Janka) I can't do that. Sorry to have wasted your time.
"Basically," our gal writes, "I feel pretty stupid about the whole thing. There were def other red flags... I have showered like 3 times and still feel nasty after figuring out it was him. I had made it clear then that I would NOT go to his apt, yet he persisted on baiting me on Sunday night. Guys like that make me want to buy a tazer....gross."
Gawker: protecting NYC women from skeevy guys since 2007. Not afraid to be servicey! |
Large-scale expression in Escherichia coli and efficient purification of precursor and active caspase-7 by introduction of thrombin cleavage sites.
Caspases are a family of cysteine proteases that have critical roles in the apoptotic pathway. Caspase-7 is a well-known apoptotic effector that cleaves a variety of cellular substrates, and is known to be an important target in the treatment of many diseases. For efficient research, large amounts of the protein are required. However, it has been difficult to obtain sufficient quantities of either the precursor or active caspase-7 from Escherichia coli strain. In the present study, we constructed thrombin-activatable caspase-7 precursors by changing the auto-activation sites of the caspase-7 precursor into sequences susceptible to thrombin cleavage. These engineered precursors were highly expressed as soluble proteins in E. coli, and were easily purified by affinity chromatography (to levels of 10-15 mg per liter of E. coli culture), and were then readily activated by treatment with thrombin. In vitro cleavage assays and kinetic analyses revealed that the engineered active caspase-7 proteins had characteristics similar to those of wild-type caspase-7. This novel method is valuable for obtaining both precursor and active caspase-7, thereby contributing to the development of caspase-7-specific drugs to treat various diseases, including cancer and neurodegenerative conditions. |
Poudel GP, Agrawal S, Dhakal S. Milker's nodule: An under‐reported and under‐diagnosed occupational infection. Clin Case Rep. 2020;8:1162--1165. 10.1002/ccr3.2850
1. INTRODUCTION {#ccr32850-sec-0001}
===============
Occupational dermatosis is described as any change in the mucocutaneous or annexes that is caused, conditioned, maintained, or aggravated by agents present in the occupational activity or working environment.[^1^](#ccr32850-bib-0001){ref-type="ref"} Milker\'s nodules is a highly contagious, Zoonotic, self‐limited disease caused by the Paravaccinia virus, acquired on the job site due to lack of use of Personal protective equipment.
We describe here a case of Milker\'s nodules with its dermatoscopy and histology features. We believe that the number of cases is greater than found in literature; as the disease is self‐limited, many do not seek medical help, making it appear relatively infrequent.
2. CASE REPORT {#ccr32850-sec-0002}
==============
A 30‐year‐old male dairy farm worker presented with the appearance of multiple painless nodules on fingers of bilateral hand for 1 month. After 7‐10 days, he developed vesicles which ruptured followed by the formation of hemorrhagic crust. There was history of discomfort and pain over the medial aspect of right arm and forearm. He did not associate any triggering factor, denied local trauma, and/or insect bite; however, a history of having similar lesions on the teats of his cow was present (Figure [1](#ccr32850-fig-0001){ref-type="fig"}).
{#ccr32850-fig-0001}
Cutaneous examination revealed firm, nontender, 3‐4 nodules with central hemorrhagic crust surrounded by well to ill‐defined erythema on the phalanges of bilateral hand (Figure [2](#ccr32850-fig-0002){ref-type="fig"}) and (Figure [3](#ccr32850-fig-0003){ref-type="fig"}) with raised temperature and mild tenderness along the medial aspect of right arm and forearm.
{#ccr32850-fig-0002}
{#ccr32850-fig-0003}
On dermatoscopy, the lesions showed an erythematous area, central ulceration, crust, yellow white streaks, brown dots, structure less whitish area partially surrounding it with erythematous ring and dot vessels (Figure [4](#ccr32850-fig-0004){ref-type="fig"}).
{#ccr32850-fig-0004}
Histopathological examination of the skin biopsy from the nodule revealed compact hyperkeratosis with focal parakeratosis, irregular acanthosis, varying degree of spongiosis with exocytosis of lypmphocytes, and dermis revealing perivascular, periadnexal and interstitial lymphohistiocytic infiltrate extending to subcutis (Figures [5](#ccr32850-fig-0005){ref-type="fig"}, [6](#ccr32850-fig-0006){ref-type="fig"}, [7](#ccr32850-fig-0007){ref-type="fig"}).
{#ccr32850-fig-0005}
{#ccr32850-fig-0006}
{#ccr32850-fig-0007}
Based on history, clinical, dermatoscopy, and histopathological examination, the diagnosis of Milker\'s nodule with lymphangitis was made.
Counseling, reassurance, and advice regarding the use of personal protective equipment while handling infected animal was done, and the patient was managed with oral amoxicillin and calvulanic acid (625 mg three times a day) for 1‐week oral NSAID (diclofenac 100 mg/d) for pain management and topical antibiotics. All lesions were healed completely in 2‐3 weeks.
3. DISCUSSION {#ccr32850-sec-0003}
=============
Milker\'s nodule is also known as pseudocowpox virus, which is caused by the Paravaccinia virus, a DNA poxvirus of the genus Parapoxvirus.[^1^](#ccr32850-bib-0001){ref-type="ref"}, [^2^](#ccr32850-bib-0002){ref-type="ref"} It is an universally distributed occupational viral skin disease, which occurs in persons who manage dairy cattle whether by touching infected udder or noses of cows or those who manipulate meat and/or contaminated objects.
The incubation period ranges from 5 to 15 days, and the number of lesions varies from one to five predominantly involving the hands and forearms, though it may also occur on the face.[^1^](#ccr32850-bib-0001){ref-type="ref"} It presents as asymptomatic one or more papules developing into reddish blue, firm, painless vesicular nodule with a ring of erythema, which passes through six clinical stages, each lasting about one week. The lesions appear as erythematous macules (Erythematous maculopapular), which become target‐shaped with central ulceration and white ring, and red periphery (Target papulovesicular lesion) and then exudative nodules characterized by loss of epidermis over the center (Acute weeping nodules). The fourth phase is the formation of dry, crusted, hard, nontender nodules with darks spots on the surface (Nodular stage). These lesions became papillomatous nodules with irregular surface (Papillomatous) and finally the lesions involute without scar (Regressive).[^3^](#ccr32850-bib-0003){ref-type="ref"}
The lesions are self‐limiting and usually disappear spontaneously within 4‐6 weeks. However, the lesions may last for months and it tends to recur in immunocompromised individuals. Uncommonly, the patients may present with fever, lymphadenopathy, lymphangitis, erythema multiforme, and secondary bacterial overgrowth of the lesions.[^1^](#ccr32850-bib-0001){ref-type="ref"}
The diagnosis of Milker\'s nodules is mostly done by the detailed history and physical examination. Some supportive investigations such as dermoscopy and histopathology features are helpful tool for the diagnosis of this condition.
The dermoscopy findings of Milker\'s nodules are generally classified into four categories: Type 1 lesions shows central yellow white area and erythematous ring outside; type 2 shows orange yellow streaks in the center with violaceous erythematous base and grayish whitish streaks around and the erythematous ring outside; ulceration in the center, yellow white ring around, and erythema ring outside present in type 3; and erythema in the center or ulcer‐crusted area and yellow white ring around in type 4. Black dot and polymorphic vessels (predominated dot and comma vessels) may also be present in different type of lesions.[^4^](#ccr32850-bib-0004){ref-type="ref"} In our case, ulceration in the center, crust and yellow white ring and erythema ring was present corresponding to the stage 3 of disease progression.
The histological examination of lesions reveals hyperkeratotosis, mild to moderate acanthosis, spongiosis, eosinophilic cytoplasm, and nuclear inclusions in the epidermis and dense lymphohistocytic infiltrates in the dermis. Depending upon the stages, some of the histologically findings may be predominant. During earlier stages namely maculopapular and target stages, vacuolization of epidermal cells with eosinophilic inclusion bodies leading to multilocular vesicles is limited to upper third of stratum Malpighi. However, throughout epidermal necrosis and massive infiltration of mononuclear cells are observed in acute weeping stage and in later stages acanthosis and vasodilation with chronic inflammatory cell infiltrate are predominant in dermis and subcutis.[^5^](#ccr32850-bib-0005){ref-type="ref"}
The confirmation of the diagnosis is made by viral isolation, starting with the tissue culture or by electron microscopy, where the virus is seen as cylindrical shape.[^6^](#ccr32850-bib-0006){ref-type="ref"} Histogenesis and viral identification via tissue culture in bovine or Rhesus monkey kidney cells are preferred if lesions are \<2 weeks however viral antigen demonstration in lesional material for older lesion.[^5^](#ccr32850-bib-0005){ref-type="ref"} PCR is the quickest and most reliable method, which can distinguish between the various subgroups of the parapoxvirus.[^7^](#ccr32850-bib-0007){ref-type="ref"}
The patients should be managed by supportive treatment, counseling and reassurance with domestic animal pet\'s treatment by vets to ensure complete management.
The most common differential diagnosis is Orf, which is also a viral skin disease caused by parapoxvirus of the Poxviridae family, which is mostly diagnosed by the history of contact with ovine or caprine herds (rather than with bovines), given that they are clinically and histopathologically undistinguished.[^8^](#ccr32850-bib-0008){ref-type="ref"} Other differential diagnoses of Milker\'s nodules include anthrax, atypical mycobacteriosis, and tularemia.
In our case, the classical lesions of target and nodular stage with dermoscopy and histological finding, resolution in 2‐3 weeks, lesions on teat of the cow, and the feature of lymphadenitis subsided within 1 week were quite characteristic of Milker\'s nodules.
4. CONCLUSION {#ccr32850-sec-0004}
=============
The diagnosis of Milker\'s nodules is usually made with clinical acumen without the necessity of elaborate and costly laboratory methods. It is also important to emphasize the use of nonpermeable gloves by handling the infected cattle until complete resolution of lesions to reduce the risk of human infection.
CONFLICT OF INTEREST {#ccr32850-sec-0005}
====================
None declared.
AUTHOR CONTRIBUTION {#ccr32850-sec-0006}
===================
SA: involved in concept, idea, and editing; GPP: involved in preparation, literature review, and processing; SD: involved in histopathological report.
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Introduction {#s1}
============
Perceived or self-rated health is widely recognized as an important indicator of health [@pone.0065858-Rohrer1], [@pone.0065858-Perruccio1] and is often used to monitor health trends in the general population [@pone.0065858-Heistaro1] as well as to assess patient-centered outcomes in clinical studies [@pone.0065858-Alonso1]. Although the need to go beyond an exclusive focus on perceptions has been pointed out [@pone.0065858-Sen1], [@pone.0065858-Salomon1], perceived health is nonetheless an important indicator variable that has been shown to predict mortality independently of the presence and severity of disease and risk factors [@pone.0065858-Idler1], as well as to predict health services utilization and health care costs [@pone.0065858-DeSalvo1], and future disability [@pone.0065858-Lee1], [@pone.0065858-Ashburner1].
Chronic conditions are among the most important predictors of perceived health [@pone.0065858-Saarni1]--[@pone.0065858-Leinonen1]. Some conditions, such as those causing pain, are known to be associated with great decrements in perceived health [@pone.0065858-vanDijk1]. We previously reported important decrements in perceived health associated with neurological conditions, depression and arthritis once the presence of other conditions had been taken into account [@pone.0065858-Alonso3]. A higher impact of mental conditions (as compared to other medical conditions) on perceived health has also been reported [@pone.0065858-Ormel1].
Prevalent conceptual frameworks and models of health propose that disability mediates the impact of chronic conditions on perceived health [@pone.0065858-Guyatt1]--[@pone.0065858-Valderas1]. A mediation model proposes a causal mechanism of relation between an independent variable (i.e., chronic conditions) which has an effect on a third explanatory variable, the mediator (i.e., disability), which in turn influences an outcome (i.e., perceived health) [@pone.0065858-Baron1]--[@pone.0065858-Pearl1]. Consistent with this model, mounting evidence shows that disability is significantly associated with perceived health both cross-sectionally [@pone.0065858-Damian1], [@pone.0065858-Lee2] and longitudinally [@pone.0065858-Leinonen1], [@pone.0065858-Lee2], [@pone.0065858-Mavaddat1]. There is also evidence that chronic conditions are significantly associated with disability [@pone.0065858-Ormel2]--[@pone.0065858-Boot1]. A few studies have assessed the mediating role of disability in the association of chronic conditions and mental health [@pone.0065858-Ormel3], [@pone.0065858-BuistBouwman1]. However, we are not aware of any systematic attempt to identify the extent to which different dimensions of disability mediate the overall associations of chronic conditions with perceived health in epidemiological samples. Such an analysis could have value in enhancing our understanding of the pathways that link chronic conditions to perceived health. In turn, this could help customizing condition-specific interventions aimed at ameliorating the disabilities that lead to significant decrements in perceived health.
In this paper we explore the extent to which a multidimensional assessment of disability mediates the associations of 19 chronic conditions (9 mental, 10 physical) on perceived health in surveys of the WHO World Mental Health (WMH) surveys initiative [@pone.0065858-Kessler1], a consortium of cross-sectional general population epidemiological surveys carried out in 22 developing and developed countries throughout the world. We focus not only on the extent to which disability mediates the total effects of each condition, but also on the relative importance of individual disability dimensions and how it varies across type of conditions. We had hypothesized that a significant proportion of the decrease in perceived health status associated to mental and physical conditions would be mediated by specific disability dimensions. We also anticipated that the pattern of disability mediation (i.e., the portion of the effect of the chronic condition on perceived health VAS score that was explained by its association with the disability dimensions and the association of the latter with perceived health) could be different for mental and for physical conditions.
Methods {#s2}
=======
Sample {#s2a}
------
A total of 23 surveys were carried out in 22 countries, 6 classified by the World Bank (2009), at the time of data collection, as low and lower-middle income (Colombia, India (Pondicherry region), Iraq, Nigeria, Peoples\' Republic of China (cities of Beijing/Shanghai and Shenzhen), and Ukraine), 5 upper-middle income countries (Brazil --Sao Paulo metropolitan area-, Bulgaria, Lebanon, Mexico and Romania) and 11 high income (Belgium, France, Germany, Israel, Italy, Japan, Netherlands, Northern Ireland, Portugal, Spain, and United States of America). Informed consent was obtained before beginning interviews, using procedures approved by the institutional review board of the organization coordinating the survey in each country (please, see additional online table). The weighted average response rate across countries was 72.0%, with country-specific response rates ranging from 45.9% (France) to 87.7% (Colombia). All surveys were based on probability samples of the country\'s adult household population that were either nationally representative (in the majority of countries) or representative of particular regions of the country (in China, Colombia, India, Japan, and Mexico). The age ranges of the sample varied across participating countries. Most countries had a minimum age of 18 years, while the minimum in Japan and Israel were 20 and 21, respectively. The upper age was unrestricted in most surveys but was 70 in China and 65 in Colombia and Mexico. Additional details about sampling and respondents are available elsewhere.
All interviews were conducted face-to-face by trained lay interviewers either using a computer assisted personal interview (CAPI) or a paper and pencil interview (PAPI). In most of the countries, except Iraq, Romania and Israel, each interview had two parts. All respondents completed Part 1, which contained core mental conditions, while all Part 1 respondents who met criteria for any core mental condition plus a random probability sub-sample of other Part 1 respondents were administered Part 2 (the latter assessing, in detail, correlates, service use, and conditions of secondary interest to the study). Data were weighted to adjust for differential probabilities of selection and to match population distributions on socio-demographic and geographic data. An additional weight was used for the over sampling of respondents for the Part 2 sample.
Updated WHO guidelines for translation and back-translations focusing on conceptual equivalence were used for all study materials. Pretesting and independent experts\' evaluations indicated equivalent measures. Certified lay interviewers were used for data collection, since they tend to achieve highly reliable measures [@pone.0065858-Fowler1]. Standardized procedures for interviewer training were followed in all settings including a certification process and a close supervision of data quality. These procedures are described in more detail elsewhere [@pone.0065858-Pennell1]. Informed consent was obtained from all respondents. Procedures for obtaining informed consent and protecting human subjects were approved and monitored for compliance by the Institutional Review Boards of the organizations coordinating the surveys in each country.
Chronic physical conditions {#s2b}
---------------------------
Physical conditions were assessed with a standard chronic conditions checklist that asked respondents if they had ever suffered from the given physical health condition, if they had the condition in the past 12 months and if they had received any treatment. Such checklists have been shown to provide more accurate and complete self-reports than as compared to open-ended questions. Methodological studies suggest a moderate to good concordance between such reports and medical records [@pone.0065858-Kriegsman1], [@pone.0065858-Baumeister1].
The ten conditions considered here are: arthritis, cancer, cardiovascular (heart attack, heart disease, hypertension, and stroke), chronic pain (chronic back or neck pain and other chronic pain), diabetes, frequent or severe headache or migraine, insomnia, neurological (multiple sclerosis, Parkinson\'s, and epilepsy or seizures), digestive condition (stomach or intestine ulcer or irritable bowel condition), and respiratory (seasonal allergies like hay fever, asthma, or COPD or emphysema). For the symptom based conditions like arthritis, chronic pain and headache, heart attack or stroke respondents were asked to report whether they had experienced these conditions. For the remaining silent conditions the question was prefaced by the phrase "*have you ever been told by a doctor or health professional that you had any of these conditions?"* The time frames varied across countries and chronic conditions: the western European countries assessed both lifetime and 12-month presence of each condition, while for the rest of the countries that used the CAPI version of the questionnaire some of the chronic conditions were only evaluated lifetime, but for problems that could have remitted, participants were asked if they still had the conditions in the past 12 months. Finally, the PAPI countries used a 12 month time frame for most symptom-based conditions and lifetime (LT) frame for the silent conditions. The 12 month time frame has been used whenever possible but, for some of the conditions inconsistent time frames were used across countries. Generally good agreement between self-report of medical diagnoses and physician or medical record confirmation of those diagnoses [@pone.0065858-Fowler1], [@pone.0065858-Pennell1].
Mental conditions {#s2c}
-----------------
Mental conditions were assessed with Version 3.0 of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI 3.0), a fully structured lay-administered interview designed to generate diagnoses of mental conditions based on the Diagnostic and Statistical Manual of the American Psychiatric Association, IV^th^ edition (DSM-IV). The mental conditions considered here are: depressive conditions (major depressive condition, minor depressive condition), bipolar disorder (mania, hypomania, bipolar I, bipolar II), panic disorder (Panic disorder, agoraphobia without panic), specific phobia, social phobia, generalized anxiety condition, post-traumatic stress disorder, alcohol abuse with and without dependence, drug abuse with and without dependence.
Only conditions present in the past 12 months are considered in this report. Generally good concordance has been found between CIDI diagnoses of anxiety and depressive conditions and independent clinical assessment [@pone.0065858-Wittchen1], [@pone.0065858-Haro1].
Perceived health {#s2d}
----------------
Overall perceived health was assessed using a visual analog scale (VAS) approach [@pone.0065858-Alonso3]. Respondents were asked to use a 0 to 100 scale where 0 represents the worst possible health a person can have and 100 represents perfect health to *"describe your own overall physical and mental health during the past 30 days"* taking into consideration all the physical and mental conditions reviewed in the survey.
Disability {#s2e}
----------
Disability was assessed with a modified version of the WHO Disability Assessment Schedule 2.0 (WHODAS) [@pone.0065858-Ustun1], [@pone.0065858-VonKorff1]. Questions were asked about difficulties in: a) understanding and communication (cognition), b) moving and getting around (mobility), c) attending personal hygiene, dressing and eating, and living alone (self-care) and d) interacting with other people (getting along). In addition, a series of questions about activity limitations days replaced the WHODAS life activities domain questions. In these questions, respondents were asked the number of days out of the past 30 that they were totally unable to carry out their normal activities or work; that they had to cut down in the activities; that they had to reduce their quality; or that they needed to exert an extreme effort to carry out their activities, due to physical or mental health problems (role functioning). Respondents were also asked about the extent of embarrassment (stigma) and discrimination or unfair treatment (discrimination) they experienced due to their health condition and, finally, they were asked about the interference of their health condition on the day to day activities of their family members (family burden). Scores on each dimension were computed, ranging from 0 to 100, where 0 indicated no disability and 100 indicated complete disability.
Statistical analysis {#s2f}
--------------------
We used SUDAAN V10.0 (RTI International, USA) to generate estimates of condition prevalence and descriptive statistics for the distributions of the continuous variables. We then used MPlus 6.0 (Muthén and Muthén, Los Angeles, CA) to conduct all multivariate analyses in parallel in the total sample and within three subsamples consisting of respondents low and lower-middle, upper-middle, and high income countries.
Path analysis was used to estimate, through simultaneous regression mediation submodels, the total, the direct, and the indirect (i.e., mediated by disability) effects of each condition in predicting VAS scores. The direct effect of each condition on perceived health VAS score is that part of its total effect which is not mediated via intervening variables. The indirect effects of each condition on VAS, via WHODAS domains, were generated as the product of regression coefficients (the regression coefficient of VAS score regressed on the WHODAS domain multiplied by the coefficient of the domain regressed on the condition). The submodels of the path analysis were embedded in a single general structural model as detailed in [**Figure 1**](#pone-0065858-g001){ref-type="fig"} (see figure legend). Note that in the general model the effects of each disorder on the mediator variables are controlled by the direct effect of the remaining disorders (thus adjusting for comorbidity) and the VAS is adjusted by the total effects of all disorders as well as sociodemographic variables (age, gender, employment status and country). The final model took into account 19 disorders and 8 mediating dimensions. For purposes of comparing the relative magnitude of the direct and indirect effects across conditions, the total effect within condition (i.e. the sum of the direct effect plus all indirect effects) was rescaled to sum up 100%. To estimate model parameters, we used the maximum likelihood estimation method. To account for the complex sample design, standard errors and statistical tests were calculated using a sandwich estimator implemented in M-PLUS, which is equivalent to the Taylor series linearization method.
{#pone-0065858-g001}
Results {#s3}
=======
A total of 51,344 respondents (Part 2 respondents) were assessed of which 16,051 were from low/lower-middle income, 10,496 from upper-middle income, and 24,797 from high income countries ([Table 1](#pone-0065858-t001){ref-type="table"}). Individuals had an average of 42 years of age, varying from an average of 37 in low/lower-middle income to an average of 46 in the high income countries. Almost 52% were female and just above a third (35.7%) were not married. The proportion of individuals with completed high school varied from 47.2% in the low/lower-middle income to 71.8% in the high income countries. Overall, 41.6% of the sample was not working (41.9% in low/lower-middle income, 46.5% in upper-middle income and 39.3% in high income countries).
10.1371/journal.pone.0065858.t001
###### Sample Characteristics per country income level. The WMH Surveys.
{#pone-0065858-t001-1}
Country N Females Not Married = \>High School Not Working Age Any Mental Any Physical Any Mental or Physical
--------------------------------- ------- ------------ ----------------- ------------------ ----------------- ------------------ ----------------- ----------------- ------------------------
**Low and Lower-middle income**
Colombia 2381 54.5 (1.5) 43.4 (1.7) 46.4 (2.3) 46.4 (2) 36.6 (0.3) 18.7 (1) 42.7 (1.3) 50.4 (1.5)
India - Pondicherry 1373 50 (1.6) 30.2 (2.1) 47 (1.9) 52.1 (1.5) 38.1 (0.6) 19 (1) 40.7 (2) 47.2 (2.1)
Iraq 4332 49.7 (1) 34.4 (1.2) 35.3 (1.1) 59.2 (1.2) 36.9 (0.4) 10.9 (0.7) 44.5 (1.1) 47.8 (1)
Nigeria 2143 51 (1.5) 39.7 (1.6) 35.6 (1.3) 31.1 (1.4) 35.8 (0.4) 6.3 (0.6) 46.2 (1.6) 49.2 (1.6)
PRC --Beijing/Shanghai 1628 47.7 (1.8) 33.4 (1.7) 55 (1.6) 41.2 (2.2) 41.2 (0.6) 6 (0.8) 53 (1.8) 54.8 (1.8)
PRC -- Shenzhen 2475 50.3 (1.6) 46.2 (1.3) 49.4 (1.5) 8.5 (0.6) 29.1 (0.3) 7.8 (0.7) 30.1 (1.2) 33.8 (1.2)
Ukraine 1719 55.1 (1.3) 34.9 (1.4) 81.9 (1.5) 45.6 (2.1) 46.1 (0.8) 20.4 (1.3) 71.3 (1.8) 75 (1.8)
**Upper-Middle income**
Brazil 2942 52.8 (1.5) 40.2 (1.6) 47.2 (1.3) 35.4 (1.1) 39.1 (0.5) 27.3 (0.8) 68.5 (2) 73.5 (1.7)
Bulgaria 2233 52.2 (1.3) 25.7 (1.6) 64.2 (1.3) 50.4 (1.9) 47.8 (0.6) 10.7 (0.6) 44.3 (1.3) 48.1 (1.4)
Lebanon 602 48.1 (2.6) 39 (3.2) 40.5 (2.8) 48.9 (2.4) 40.3 (0.9) 10 (1.5) 38.8 (2.1) 43.8 (2.5)
Mexico 2362 52.3 (1.9) 32.7 (1.5) 31.4 (1.7) 41.6 (1.6) 35.2 (0.3) 12.7 (0.8) 35 (1.8) 40.7 (1.8)
Romania 2357 52.4 (1.3) 30.4 (1.2) 49.3 (1.7) 60.7 (1.3) 45.5 (0.5) 7 (0.6) 48.1 (1.3) 50.6 (1.3)
**High income**
Belgium 1043 51.7 (2.4) 30.2 (1.7) 69.7 (3.7) 42.2 (1.4) 46.9 (0.7) 13.8 (1.7) 48.8 (2.2) 54.1 (2.4)
France 1436 52.2 (1.8) 29 (1.8) . (.) 37.9 (1.8) 46.3 (0.7) 18.5 (1.3) 52.7 (2.2) 59.5 (2.3)
Germany 1323 51.7 (1.4) 36.7 (1.7) 96.4 (0.9) 43.5 (2.1) 48.2 (0.8) 10.9 (1.3) 49.7 (2.4) 54.2 (2.4)
Israel 4859 51.9 (0.4) 32.2 (0.7) 78.3 (0.7) 39.8 (0.8) 44.4 (0.2) 10.7 (0.5) 55.5 (0.8) 58 (0.8)
Italy 1779 52 (1.5) 33.3 (1.6) 39.4 (1.8) 46.1 (1.7) 47.7 (0.6) 8.9 (0.7) 50 (1.8) 52.9 (1.7)
Japan 1682 53 (1.9) 31.2 (1.4) 71.6 (1.4) 36.5 (1.8) 51.2 (0.7) 7.6 (0.6) 52.8 (1.8) 55.6 (1.9)
Netherlands 1094 50.9 (2.2) 27.9 (2.6) 69.7 (1.8) 37.7 (2.6) 45 (0.8) 13.5 (1) 48.5 (2.3) 52.8 (2.2)
N.Ireland 1708 51 (1.4) 40.4 (1.8) 88.7 (1) 37.4 (1.9) 45.3 (0.6) 19.1 (1.5) 54.4 (1.9) 60.6 (1.8)
Portugal 2060 51.9 (1.5) 30.4 (1.4) 54.8 (1.7) 40.3 (1.5) 46.5 (0.7) 21.8 (0.9) 55.1 (1.6) 63.1 (1.6)
Spain 2121 51.4 (1.7) 34.7 (1.5) 41.7 (1.5) 49.6 (1.8) 45.6 (0.7) 9.9 (0.9) 42.8 (1.5) 47.1 (1.5)
United States 5692 53.1 (1) 44.1 (1.2) 83.2 (0.9) 33.2 (1.1) 45 (0.5) 24.5 (0.8) 70.1 (1) 75 (1)
All countries 51344 51.8 (0.3) 35.7 (0.3) 58.6 (0.4) 41.6 (0.3) 42.3 (0.1) 14.4 (0.2) 51.4 (0.4) 55.8 (0.4)
comparison among countries 1.2 (0.2) 13.8 (\<0.0001) 165.6 (\<0.0001) 63 (\<0.0001) 187.9 (\<0.0001) 59.8 (\<0.0001) 38.6 (\<0.0001) 40.4 (\<0.0001)
High income 24797 52.1 (0.4) 35.4 (0.5) 71.8 (0.5) 39.3 (0.5) 46 (0.2) 15.7 (0.3) 56 (0.5) 60.5 (0.5)
Upper-Middle income 10496 52.1 (0.7) 33.3 (0.7) 47.2 (0.8) 46.5 (0.7) 41.5 (0.2) 14.8 (0.4) 49.3 (0.8) 53.6 (0.7)
Low and Lower-middle income 16051 51.1 (0.6) 37.9 (0.6) 47.2 (0.6) 41.9 (0.6) 37 (0.2) 12.1 (0.3) 45.6 (0.6) 49.8 (0.6)
comparison low, middle, high 1.2 (0.3) 12.6 (\<0.0001) 582.2 (\<0.0001) 36.9 (\<0.0001) 633 (\<0.0001) 31.4 (\<0.0001) 85.5 (\<0.0001) 89.6 (\<0.0001)
Physical chronic conditions were more prevalent than mental conditions, with 12 month prevalence ranging from a lowest of 30.1% (Shenzhen, China) to a highest of 71.3% in Ukraine and 70.1% in the United States. The prevalence of mental conditions ranged from a lowest of 6% in Beijing/Shanghai (China) to a highest of 27.3% in Sao Paulo metropolitan area (Brazil) and 24.5% in the United States. There was a trend towards higher prevalence of conditions among in higher income countries.
Chronic pain was the most common condition in low/lower-middle income (21.9%), in upper-middle income (20.5%), and in high income (21.6%) countries. In the latter, cardiovascular conditions (19.3%) were also very common. Other common physical conditions in all countries were respiratory, cardiovascular, arthritis and headache/migraine. The prevalence of any physical condition ranged from 56% in high income to 45.6% in low/lower-middle income countries. Any mental condition ranged from 15.7% (high income) to 12.1%, (low/lower middle income) (data not shown but available upon request).
Distribution of WHODAS scores {#s3a}
-----------------------------
[Table 2](#pone-0065858-t002){ref-type="table"} shows the proportion of respondents with difficulties on each of the WHODAS dimensions for the overall sample and for each income country category. Over a third of respondents (35.7%) had some difficulty in the WHODAS (score\>0), the frequency being considerably higher among respondents from high income countries (46.5%) than for those in other countries (22.2% and 28%). Role functioning dimension was the most frequently affected dimension (31.7%) in all income country categories (from 42% to 18.3%). Mobility and stigma showed the second most frequent difficulties (11.4% and 8.3%, respectively in the overall sample), while self-care was the least frequently affected (3.4%).
10.1371/journal.pone.0065858.t002
###### Distribution of the WHODAS dimension scores by income level. The WMH Surveys.
{#pone-0065858-t002-2}
Across non-zero
------------------------------------------- ------------- ------------- ----------------- ----- ------ ------
**Overall sample**
Cognition 6.9 (0.14) 0.8 (0.03) 12 (0.32) 1.7 5 15.6
Mobility 11.4 (0.19) 3.2 (0.07) 28.2 (0.48) 5 16.7 50
Self-care 3.4 (0.1) 1 (0.05) 28.3 (1.12) 5 16.1 50
Getting along 3.9 (0.11) 0.6 (0.03) 15.8 (0.54) 2.3 7.5 22.2
Role functioning 31.7 (0.3) 9 (0.14) 28.5 (0.36) 3.2 10.8 46.7
Family burden 8.1 (0.15) 3.7 (0.08) 45.2 (0.46) 25 50 50
Stigma 8.3 (0.16) 4 (0.08) 48.7 (0.44) 25 50 75
Discrimination 3.5 (0.1) 1.7 (0.05) 47.1 (0.69) 25 50 50
Global Whodas 35.7 (0.3) 2.9 (0.05) 8.2 (0.12) 0.6 2.5 10
**High income countries**
Cognition 7.9 (0.2) 1 (0.04) 12.5 (0.4) 1.7 5 16.7
Mobility 14.6 (0.3) 4.4 (0.13) 30.3 (0.64) 5 19.4 53.3
Self-care 4.1 (0.15) 1.3 (0.08) 30.3 (1.5) 5 16.7 50
Getting along 4.8 (0.17) 0.8 (0.04) 15.6 (0.59) 2.3 7.5 21.7
Role functioning 42 (0.43) 10.7 (0.21) 25.5 (0.45) 3.2 6.7 37.5
Family burden 8.7 (0.22) 3.9 (0.11) 45.2 (0.65) 25 50 50
Stigma 7.6 (0.19) 3.6 (0.1) 46.8 (0.68) 25 50 50
Discrimination 2.8 (0.11) 1.3 (0.06) 48.2 (1.05) 25 50 75
Global Whodas 46.5 (0.43) 3.6 (0.08) 7.8 (0.15) 0.6 1.7 10
**Upper-middle income countries**
Cognition 5.8 (0.3) 0.8 (0.06) 13.3 (0.79) 1.9 5 18.3
Mobility 7.8 (0.3) 2.2 (0.11) 28.8 (1.01) 5.6 16.7 50
Self-care 2.1 (0.17) 0.7 (0.06) 31.2 (2.39) 6.7 16.7 50
Getting along 2.2 (0.18) 0.5 (0.06) 22.8 (1.84) 4 15 36.7
Role functioning 18.3 (0.56) 7.1 (0.27) 38.8 (1.21) 8.3 25 60
Family burden 7.7 (0.27) 3.5 (0.14) 45.3 (0.9) 25 50 50
Stigma 9.1 (0.32) 4.8 (0.18) 52.3 (0.76) 25 50 75
Discrimination 4.3 (0.2) 2 (0.11) 47.3 (1.17) 25 50 75
Global Whodas 22.2 (0.58) 2.3 (0.09) 10.1 (0.35) 1.3 5 13.3
**Low and lower-middle income countries**
Cognition 6.1 (0.27) 0.6 (0.05) 10.4 (0.68) 1.5 4.4 12.5
Mobility 8.7 (0.29) 2 (0.09) 22.4 (0.86) 3.9 11.1 33.3
Self-care 3.2 (0.2) 0.7 (0.09) 22.9 (2.16) 3.3 10 32.5
Getting along 3.5 (0.2) 0.5 (0.05) 13.1 (1.16) 2 5.3 16.7
Role functioning 24.6 (0.46) 7.8 (0.23) 31.6 (0.69) 6.7 16.7 49.2
Family burden 7.4 (0.28) 3.3 (0.15) 45.2 (0.92) 25 50 50
Stigma 8.9 (0.35) 4.3 (0.18) 48.7 (0.82) 25 50 75
Discrimination 4.3 (0.23) 1.9 (0.11) 45.8 (1.26) 25 50 50
Global Whodas 28 (0.48) 2.3 (0.08) 8.2 (0.23) 1.3 3.5 10.3
[Table 2](#pone-0065858-t002){ref-type="table"} also shows the mean scores in each WHODAS dimension and the global score. For the latter, mean scores were higher for high income countries (3.6) than for upper-middle and low and lower-middle income countries (2.3). But mean global WHODAS scores across those with any difficulty tended to be higher for upper-middle income (10.1) and low/lower-middle income (8.2) than for high income countries (7.8).
Distribution of perceived health VAS score {#s3b}
------------------------------------------
As shown in more detail in a previous WMH report [@pone.0065858-Alonso3], the mean VAS score was 81.0 in the overall sample. Respondents with mental conditions showed lower mean perceived health (72.2) than those with physical conditions (75). As shown in [Table 3](#pone-0065858-t003){ref-type="table"}, these trends are consistent across all country income groups.
10.1371/journal.pone.0065858.t003
###### Perceived health visual analogue scale (VAS) scores by country income level.
{#pone-0065858-t003-3}
All countries High Middle Low
---------------------------------- --------------- ------ -------- ------ ------------ ------ ------- ------ ------------ ------ ------- ------ ------------ ------ ------- ------
Overall sample 81 (0.1) 70 90 95 80.7 (0.2) 74.4 89.82 90 81 (0.3) 70 89.85 99.5 81.6 (0.2) 70 90 99.8
Any Mental condition 72.2 (0.3) 59.9 79.94 89.9 72.6 (0.4) 60 79.9 89.9 71.6 (0.7) 59.1 79.94 89.7 71.9 (0.7) 59.8 79.06 89.2
Any Physical condition 75 (0.2) 60 79.96 90 76 (0.2) 69.1 79.95 89.7 73.2 (0.5) 60 79.95 89.9 74.3 (0.4) 59.9 79.87 90
Any Mental or Physical condition 75.5 (0.2) 64.9 79.97 90 76.4 (0.2) 69.2 79.96 89.9 73.8 (0.5) 60 79.96 89.9 74.9 (0.4) 60 79.88 90
The WMH Surveys.
Direct and indirect (disability mediated) effects of conditions on perceived health {#s3c}
-----------------------------------------------------------------------------------
[Table 4](#pone-0065858-t004){ref-type="table"} presents the association of mental conditions and chronic physical conditions with VAS score for the overall sample. Total effects are highest for neurological conditions, with an average decrement of 9.8 points on the VAS, depression (8.2) and bipolar disorder (8.1). There is considerable variation across conditions in the extent to which total effects are mediated by WHODAS scores. The fourth column shows the proportion of overall indirect effects to total effects. Indirect effects tend to represent a lower proportion (among significant percentages in column 4, ranging from 19.4% to 84.0%, with a median of 36.8%, IQR = 31.2 to 51.5) of the total effect of the conditions on the VAS. Of notice some effects are non significant. These proportions can be visualized in [Figure 2](#pone-0065858-g002){ref-type="fig"}, where the total effect of each condition on the VAS is broken down into direct (shown in white) and indirect (in black) effects. In general, mental conditions tend to show higher proportions of indirect effects mediated by disability dimensions, with the highest values for PTSD (84.0%), GAD (63.7%), panic (53.1%), and bipolar disorder (47.0%). The chronic physical conditions with the highest proportions of total effects mediated by disability include cancer (78.9%), neurological conditions (57.6%), and insomnia (50.0%). Alcohol abuse and drug abuse are the only conditions considered here for which indirect effects through WHODAS scores are not statistically significant. Once adjusted by the remaining WHODAS dimensions and disorders, the dimensions most often associated with significant mediating effects across the 19 conditions are role functions (89.5%), family burden (84.2%), stigma (79.0%), mobility (73.7%), cognition (68.4%), and self-care (42.1%).
{#pone-0065858-g002}
10.1371/journal.pone.0065858.t004
###### Effects (direct and indirect via WHODAS dimension scores) of conditions on perceived health VAS, overall sample.
{#pone-0065858-t004-4}
Indirect effects via each WHODAS dimension[1](#nt104){ref-type="table-fn"}
------------------------------ ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------- ---------------- ---------------- ---------------------------------------------------------------------------- ---------------- ---------------- ---------------- ---------------- ----------------
Alcohol Abuse −2.94 (0.8)\* −3.03 (0.76)\* 0.09 (0.25) −3.16 (8.83) 0 (0.02) 0.32 (0.06)\* 0.03 (0.02) −0.11 (0.11) −0.04 (0.06) −0.1 (0.08)
Bipolar −8.09 (1.28)\* −4.29 (1.01)\* −3.8 (0.73)\* 47.02 (7.38)\* −0.48 (0.13)\* −0.26 (0.16) −0.1 (0.08) −1.22 (0.24)\* −0.86 (0.19)\* −0.77 (0.2)\*
Depression −8.17 (0.42)\* −5.17 (0.4)\* −3 (0.21)\* 36.75 (2.6)\* −0.27 (0.06)\* −0.31 (0.07)\* −0.05 (0.02)\* −1.08 (0.1)\* −0.54 (0.08)\* −0.68 (0.09)\*
Drug Abuse −3.71 (1.49)\* −3.04 (1.37)\* −0.67 (0.6) 17.98 (14.74) −0.09 (0.06) 0.13 (0.1) 0.03 (0.02) −0.32 (0.22) −0.28 (0.2) −0.09 (0.17)
Generalized Anxiety −5.25 (0.93)\* −1.91 (0.75)\* −3.34 (0.55)\* 63.66 (9.77)\* −0.28 (0.08)\* −0.49 (0.15)\* −0.06 (0.04) −1.07 (0.2)\* −0.73 (0.16)\* −0.66 (0.14)\*
Panic Disorder −6.3 (0.86)\* −2.96 (0.73)\* −3.34 (0.45)\* 53.06 (7.06)\* −0.33 (0.09)\* −0.39 (0.11)\* −0.05 (0.03) −1.1 (0.17)\* −0.61 (0.13)\* −0.8 (0.14)\*
Posttraumatic Stress −5.16 (0.91)\* −0.83 (0.8) −4.33 (0.59)\* 84 (13.49)\* −0.43 (0.11)\* −0.79 (0.16)\* −0.1 (0.05) −1.49 (0.22)\* −0.78 (0.16)\* −0.69 (0.15)\*
Social Phobia −3.07 (0.68)\* −2.01 (0.62)\* −1.06 (0.3)\* 34.61 (9.81)\* −0.18 (0.06)\* −0.01 (0.07) 0.03 (0.02) −0.32 (0.1)\* −0.27 (0.09)\* −0.26 (0.09)\*
Specific Phobia −2.26 (0.48)\* −1.67 (0.43)\* −0.59 (0.23)\* 26.03 (8.92)\* −0.03 (0.02) 0 (0.06) 0.01 (0.01) −0.22 (0.09)\* −0.19 (0.06)\* −0.15 (0.06)\*
Headache/Migrane −4.83 (0.34)\* −3.31 (0.31)\* −1.52 (0.14)\* 31.43 (2.91)\* −0.12 (0.03)\* −0.08 (0.04) −0.03 (0.01)\* −0.54 (0.06)\* −0.33 (0.05)\* −0.39 (0.05)\*
Insomnia −6.18 (0.52)\* −3.09 (0.47)\* −3.09 (0.25)\* 49.99 (4.3)\* −0.21 (0.06)\* −0.64 (0.08)\* −0.07 (0.03)\* −1.03 (0.11)\* −0.56 (0.08)\* −0.52 (0.08)\*
Neurological −9.82 (1.12)\* −4.17 (0.93)\* −5.65 (0.78)\* 57.55 (6.82)\* −0.37 (0.1)\* −1.45 (0.29)\* −0.24 (0.11)\* −1.58 (0.26)\* −0.84 (0.18)\* −1.06 (0.21)\*
Arthritis −5.47 (0.38)\* −3.46 (0.34)\* −2.01 (0.15)\* 36.76 (2.77)\* −0.04 (0.01)\* −0.65 (0.07)\* −0.05 (0.02)\* −0.64 (0.07)\* −0.24 (0.04)\* −0.36 (0.05)\*
Back/Neck Pain −6.56 (0.31)\* −4.15 (0.28)\* −2.41 (0.13)\* 36.77 (1.93)\* −0.07 (0.02)\* −0.62 (0.06)\* −0.04 (0.02)\* −0.95 (0.07)\* −0.32 (0.04)\* −0.4 (0.05)\*
Cancer −2.67 (0.86)\* −0.56 (0.76) −2.11 (0.37)\* 78.9 (22.6)\* −0.08 (0.05) −0.64 (0.14)\* −0.05 (0.03) −0.86 (0.15)\* −0.34 (0.09)\* −0.12 (0.08)
Cardiovascular −5.8 (0.35)\* −3.59 (0.33)\* −2.22 (0.15)\* 38.17 (2.75)\* −0.06 (0.02)\* −0.65 (0.07)\* −0.07 (0.03)\* −0.69 (0.07)\* −0.33 (0.05)\* −0.39 (0.05)\*
Diabetes −5.86 (0.65)\* −3.81 (0.57)\* −2.05 (0.27)\* 35 (4.45)\* −0.11 (0.03)\* −0.59 (0.1)\* −0.07 (0.03)\* −0.81 (0.12)\* −0.25 (0.06)\* −0.21 (0.06)\*
Digestive −4.06 (0.59)\* −2.8 (0.52)\* −1.26 (0.26)\* 31.01 (5.79)\* −0.01 (0.02) −0.22 (0.08)\* −0.02 (0.01) −0.47 (0.11)\* −0.24 (0.07)\* −0.29 (0.07)\*
Respiratory −1.49 (0.31)\* −1.2 (0.27)\* −0.29 (0.11)\* 19.4 (6.72)\* −0.02 (0.01) −0.1 (0.04)\* 0 (0.01) −0.17 (0.05)\* −0.02 (0.03) 0.01 (0.03)
**Direct effects of scales** Cognition: −0.12 (0.03)\* Mobility: −0.16 (0.01)\* Self-care: −0.05 (0.02)\* Getting along: −0.01 (0.03)Role functioning: −0.12 (0.01)\* Family burden: −0.11 (0.01)\* Stigma: −0.11 (0.01)\* Discrimination: −0.02 (0.02)
WMH surveys.
p-value\<0.05.
Only dimensions with statistically significant effect are included. Getting along and Discrimination not statistically significant.
[Figure 3](#pone-0065858-g003){ref-type="fig"} shows the relative importance of each disability dimension (adjusted by the rest of dimensions and comorbidity) in the disorder indirect effects on VAS scores. Thus, the 100% is the overall indirect effect of each condition, and the sections correspond to the different disability dimensions. Only the conditions with significant overall indirect effects are considered. It can be observed that role functioning is the most important mediator for all of the conditions with the exception of arthritis. The contribution of role functioning to the overall indirect effects ranges from 29% to 57%, and tends to be a bit more important among physical (median 36.5%, IQR = 32.4 to 39.3) than among mental conditions (median 32.9%, IQR = 32.0 to 35.2).
{#pone-0065858-g003}
The differential disability mediation pattern for physical and mental conditions is evident for mobility, with a median of 27.2% of indirect effects for physical conditions versus 10.3% for mental. Conversely, stigma and family burden tend to be more important mediators of perceived health for mental conditions (medians for stigma are 22.7% for mental and 17.2% for physical, and for family burden, 21.7% and 15.0%, respectively). Cognition and self care have a low contribution to the indirect effects (median across all conditions 6.6% and 1.85%, respectively).
[Tables S1](#pone.0065858.s001){ref-type="supplementary-material"}, [S2](#pone.0065858.s002){ref-type="supplementary-material"}, and [S3](#pone.0065858.s003){ref-type="supplementary-material"} are equivalent to [Table 4](#pone-0065858-t004){ref-type="table"} but restricting the sample to each of the three income country level groups. While all the total effects are statistically significant in the whole sample, not all of them are significant at the income country level. Posttraumatic stress has the highest proportion of indirect over total effects across mental conditions in the three groups. Neurological has the highest proportion for low/lower-middle and upper-middle income countries across physical conditions, while the corresponding one for high income countries is cancer.
The contributions of overall indirect to total effects among the nineteen conditions are shown in column 4 of each table of supporting information. These contributions range (among significant proportions): for high income countries, from 33.5% to 90.6%, with a median of 42.6% (IQR = 35.2--54.5); for upper-middle income countries, from 16.7% to 61.1%, median 33.2% (IQR = 26.5--48.6), and for low/lower-middle income countries, from 20.5% to 122.6%, median 38.7%, (IQR = 25.8--45.9). Hence, high income countries show the highest indirect, disability meditated, contribution.
Income country level information corresponding to [Figure 2](#pone-0065858-g002){ref-type="fig"} (the proportion of indirect specific over the overall indirect effect) indicate that in all income groups, mobility has a higher contribution in physical conditions, and the indirect effects of family burden and stigma are higher among mental conditions. While role functioning is also the most important dimension for high and low/lower-middle income countries (median percentages and IQRs are 36.2 (32.9--40.8) and 35.9 (30.0--39.0), respectively), for middle-income countries it is stigma: median percentage 38.8, IQR = (31.4--45.1). (Data not shown but available on request.)
Discussion {#s4}
==========
In this international study, we found that over a third (median of 36.8% with an IQR of 31.2% to 51.5%) of the total decrement in perceived health associated with common conditions is mediated by the disabilities assessed in the WHODAS. The magnitude of this mediated effect is exactly the same for mental disorders and for physical conditions. We also found that role functioning is the predominant dimension which indirectly accounts for the association of all the conditions with perceived health. While mobility is the second most important mediator in the case of chronic physical conditions, for mental conditions stigma and family burden are more important mediators. These results are not only statistically significant, but substantially relevant given the size and the consistency of the associations found. Taken together, these results confirm our a priori hypotheses suggesting that disability dimensions mediate the decrease of perceived health associated to chronic conditions and that the mediating dimensions are different for mental and physical conditions. Of notice these results are very similar across the three levels of country income. The fact that more than one third of perceived health decrements associated with common conditions is attributable to disability dimensions should call attention of the potential interest of assessing disability as well as to try to improve it, to ameliorate the health status of individuals with chronic conditions. That would require a systematic evaluation of disability dimensions in order to identify potential beneficial interventions.
To our knowledge, the mediating role of disability on perceived health has never been reported for samples of the general population representing so many countries worldwide for the large range of conditions and disability dimensions assessed here. Nevertheless, many studies have previously shown an association between particular dimensions of disability and perceived health, in samples of patients with particular diseases. For instance, social functioning is an important determinant of perceived health among heart failure patients [@pone.0065858-Carlson1] while physical ability has an important role on perceived health among spinal cord injury patients [@pone.0065858-Machacova1]. And for individuals with major depressive episode, cognition and embarrassment seem to be more relevant disability dimensions [@pone.0065858-BuistBouwman1]. Our results represent a first systematic attempt to disentangle the association between a range of chronic conditions and perceived health considering a comprehensive range of disability indicators. And they indicate that, on average, the disability mediated effect on perceived health is substantial and similar for the 9 mental conditions and the 10 physical conditions analyzed. Nevertheless, the type of disability dimension which mediates such effect tends to be different for physical and for mental conditions. Moreover, there is variation across individual disorders in the extent to which their impact on perceived health is mediated by disability dimensions. More research is needed for further understanding the underlying process of perceived health and disability evaluations and how they may differ by different levels of health.
Mobility disability is a frequent mediator of the effect of chronic physical conditions on perceived health (median value of 10.2% of the total effect), while this dimension is much less important for mental conditions (3.2%). Many of the physical conditions considered in our study imply either pain (arthritis, back-neck pain) or impairment on the extremities and their functional performance (neurological conditions, cardiovascular, respiratory), or general weakness (cancer and others). All of which have an impact on the mobility function and modify the perception of health of the individual [@pone.0065858-Alonso2], [@pone.0065858-Alonso3] [@pone.0065858-Garin1]. On the other hand, this disability dimension is not a very relevant mediator of the impact of mental conditions on perceived health, while family burden and stigma are. The empirical direct and indirect associations described here provide a textured picture of the ways health conditions impact on health perceptions and the role of functioning and disability. This might be important beyond description and might help guiding therapeutic efforts towards particular disabilities. For instance, in a descriptive study of breast cancer survivors it was estimated that potential interventions including physical mobility could prevent decreases in self-rated health among breast cancer survivors [@pone.0065858-Schootman1]. Also, the use of specific clinical problem-solving tools for physical and rehabilitation medicine could be liaised with assessments of perceived health [@pone.0065858-Steiner1]. Consistent with previous work [@pone.0065858-BuistBouwman1], our data suggest that assessing stigma and family burden and trying to combat them can limit the decrements in perceived health of individuals with mental conditions. The type of relationships described here for the general adult population suggests that a systematic assessment of disability might help identifying areas of needed improvement for individuals with chronic conditions. Our results also suggest that effectively addressing disability should have a noticeable positive impact on the overall perception of health of the general population.
One remarkable finding of this study is the consistency of results across income country levels. We did find differences in the prevalence of disability: individuals in high income countries were twice as much likely to endorse any WHODAS disability than those in upper-middle or low and lower-middle income countries. These differences are consistent with previous reports in the literature indicating that cultural and work-related issues as well as differential access to health and social services could cause higher rates of disability in developed countries [@pone.0065858-Madan1], [@pone.0065858-Sokka1]. In contrast, perceived health levels were very similar across countries (see [Table 3](#pone-0065858-t003){ref-type="table"}), both in the general population and among individuals with chronic conditions. The proportion of perceived health accounted by disability is very consistent across income country levels, both for the overall WHODAS and for that of the specific dimensions. Only marginal departures were found in low and lower-middle income countries, with a higher frequency of non statistical significant associations, due in part to a smaller sample size. This substantial homogeneity across countries does not mean, on the other hand, that local culture can be ignored. The need to take into account ethnic, cultural, and social dimensions in combating disability [@pone.0065858-Imrie1]--[@pone.0065858-Coggon1] is well-established.
Our results must be interpreted taking into account the following limitations. First, chronic physical conditions and mental conditions were differently assessed. The latter were measured with a standard diagnostic instrument, the CIDI, with high levels of reliability and acceptable validity for research purposes. Conversely, chronic physical conditions were self-reported by respondents. Although we used standardized questions which have shown acceptable validity levels [@pone.0065858-Fowler1], [@pone.0065858-Pennell1], misclassification cannot be ruled out, in particular, underreporting of physical health conditions in countries with lower access to health care. Second, we did not assess some particularly disabling brain conditions such as non-affective psychotic conditions and dementia [@pone.0065858-Murray1]. Our study, therefore, likely underestimates disability caused by mental conditions. Third, only 12-month physical and mental conditions were considered in this study, to increase the accuracy of recalls. Nevertheless, while physical conditions and mental conditions were assessed in the 12 months previous to the interview, both overall perceived health (VAS) and the WHODAS questions referred to the 30 days preceding the interview. Due to different time frames it is not possible to definitively relate either the health status nor the disability reported by the respondents to their underlying mental of physical health condition for the preceding 12 months. Nevertheless, because both, the VAS and the WHODAS use the same recall period, any such bias should not influence our analyses of the intermediating role of disability in the impact of conditions on perceived health. Similarly, we were not able to assess the duration of the disability. It has been suggested that age at disability onset may impact self-reported general health and should be considered when analyzing HRQOL differences within people with disabilities [@pone.0065858-Jamoom1]. Finally, an important consideration is the difficulty to differentiate the nature of conditions, symptoms, function and perceptions, as well as the need to refine the mediating and/or moderating nature of the described associations [@pone.0065858-Wang1].
Implications {#s4a}
------------
Our results, which are basically descriptive, call attention on the need to assess and consider disability to better understand how perceived health is influenced by common mental and physical conditions. More than a third of the decrements in perceived health are mediated by disability dimensions and would not be a direct effect of these conditions. This should call attention to the importance of addressing disability to increase health status among individual with common conditions. While disability can be more or less obviously related with the index condition, a systematic evaluation of disability could be beneficial. While role limitation and mobility are the disability most frequently mediating the effect of chronic physical conditions, stigma is an important mediator dimension for mental disorders. Measuring stigma among individuals with mental disorders should improve understanding of their perceived health reports. If the association of mental disorders and stigma is causal, combating stigma effectively could translate in gains in perceived health of individuals with mental disorders. Taken together, the findings described here suggest that there is need to learn more about the strength and ways of indirect association between chronic conditions and perceived health. In particular, evaluating whether interventions addressed to improve specific disabilities may improve perceived health of individuals with common chronic conditions beyond benefits that would be obtained with the usual treatment for these conditions.
Supporting Information {#s5}
======================
######
**Effects (direct and indirect via WHODAS) of conditions on perceived health VAS. WMH [high income]{.ul} countries.** \* p-value\<0.05. ^1^ Only dimensions with statistically significant effect are included. Getting along and Discrimination not statistically significant.
(DOC)
######
Click here for additional data file.
######
**Effects (direct and indirect via WHODAS) of conditions on perceived health VAS. WMH surveys [middle income]{.ul} countries.** \* p-value\<0.05, ^1^ Only dimensions with statistically significant effect are included. Cognition, Self-care, Getting along and Discrimination not statistically significant.
(DOC)
######
Click here for additional data file.
######
**Effects (direct and indirect via WHODAS) of conditions on perceived health VAS. WMH surveys [low income]{.ul} countries.** \* p-value\<0.05, ^1^ Only dimensions with statistically significant effect are included. Self-care, Getting along and Discrimination not statistically significant.
(DOC)
######
Click here for additional data file.
We gratefully acknowledge Dr. Carlos García-Forero for his invaluable comments on statistical analysis modeling and for producing Figure 1. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on data analysis. We also thank Ms. Raquel Gómez and Carme Gasull for their help in the preparation of the manuscript. A complete list of all within-country and cross-national WMH publications can be found at <http://www.hcp.med.harvard.edu/wmh/>.
[^1]: **Competing Interests:**Dr. Kessler has been a consultant for AstraZeneca, Analysis Group, Bristol-Myers Squibb, Cerner-Galt Associates, Eli Lilly & Company, GlaxoSmithKline Inc., HealthCore Inc., Health Dialog, Hoffman-LaRoche, Inc., Integrated Benefits Institute, John Snow Inc., Kaiser Permanente, Matria Inc., Mensante, Merck & Co, Inc., Ortho-McNeil Janssen Scientific Affairs, Pfizer Inc., Primary Care Network, Research Triangle Institute, Sanofi-Aventis Groupe, Shire US Inc., SRA International, Inc., Takeda Global Research & Development, Transcept Pharmaceuticals Inc., and Wyeth-Ayerst. Dr. Kessler has served on advisory boards for Appliance Computing II, Eli Lilly & Company, Mindsite, Ortho-McNeil Janssen Scientific Affairs, Johnson & Johnson, Plus One Health Management and Wyeth-Ayerst. Dr. Kessler has had research support for his epidemiological studies from Analysis Group Inc., Bristol-Myers Squibb, Eli Lilly & Company, EPI-Q, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Janssen Scientific Affairs., Pfizer Inc., Sanofi-Aventis Groupe, Shire US, Inc., and Walgreens Co. Dr. Kessler owns 25% share in DataStat, Inc. This study was partly funded by Eli Lilly and Company, Ortho-McNeil Pharmaceutical, Inc., GlaxoSmithKline, and Bristol-Myers Squibb. The ESEMeD project is partly funded by an unrestricted educational grant from GlaxoSmithKline. The Lebanese National Mental Health Survey is partly supported by unrestricted grants from Janssen Cilag, Eli Lilly, GlaxoSmithKline, Astra Zeneca, Hikma Pharm and Novartis. The Romania WMH study projects "Policies in Mental Health Area" and "National Study regarding Mental Health and Services Use with technical support of SC. Cheyenne Services SRL. Statistics Netherlands and were partly funded by supplemental support of Eli Lilly Romania SRL. There are no patents, products in development or marketed products to declare. This does not alter the authors\' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
[^2]: Conceived and designed the experiments: JA SC RCK. Analyzed the data: JA GV ND SC EB RB JH RCK. Acquisition of data: JA GV YH LHA EB RB JF SF GG OG JMH HH CH NI SL DL JPL HM MEM SO JH JAP NI MX RCK. Drafting the article: JA GV ND SC YH LHA EB RB JF SF GG OG JMH HH CH NI SL DL JPL HM MEM SO JH JAP NI MX RCK. Final approval: JA GV ND SC YH LHA EB RB JF SF GG OG JMH HH CH NI SL DL JPL HM MEM SO JH JAP NI MX RCK.
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fred thompson
You needn’t be an employee at Sterling Cooper to appreciate the value of a well-made American cocktail. For our money, bourbon is one of the best ways to get there from here. Happily, food writer and chef Fred Thompson agrees and has thus served up a definitive selection of recipes to utilize and improvise on... |
About Small Failures:
Small Failures originally set out to prove that living sustainably and living well are not mutually exclusive. My regular posting lasted about a year, until I was in a gnarly car accident. Since then, Small Failures has been on hiatus.
Jess' Other Blog:
Visit me at the Roughstock Library, where I currently cover messaging and communications. Recent posts include:
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May 16, 2007
[Full disclosure: I received this product free of charge. Do with that info what you will.]
I generally avoid buying decorative items that espouse some political bent; I don't have bumper stickers on my car (yes, I have a car—boo, hiss—and yes, I have a small Red Sox stickah on it), I don't have buttons and pins all over my bag, and I don't wear t-shirts with philosphical statements printed across the chest. Until recently.
When I was contacted by artist Lee Tracy about her new line of bamboo, hand-screened shirts, I was a little skeptical. I get a lot of emails about new "green" products and the bulk of them lead to nothing more than claims of carbon neutrality or some such token gesture. Thus far I have simply avoided the whole thing by reviewing products very, very irregularly. But as always, I took a look around the website and was surprised at what I found.
First and foremost, I actually liked the designs offered. This was hand-printed, custom art, and it was clear that they were made with care and respect for the craft of printing (this is actually very important to me as a graphic designer). I wasn't sold on the concept of "wearable wisdom" that drives the company's commitment to social responsibility, though (see first paragraph). Then I read that $5 of each t-shirt sale goes directly to one of several very cool nonprofits. Then I read a list of incredibly impressive facts about bamboo and bamboo clothing. Then I read about how everything was packaged with ecological care. It went on and on.
So I decided to see just how normal a bamboo t-shirt is. Before placing my order, though, Tracy mailed out a shirt for me to "experience." It arrived inside a plain cotton tote that I now use for hauling veggies around from the farmers market (bonus!). The shirt was a large (I'm paranoid about undersizing), but a little too large for my 5' 4" frame. Dang.
It was also incredibly soft and the colors were intense (if I recall, Tracy mentioned giving it a double blast of ink). One problem, though: the fabric was so thin that I was showing a little more than I would have liked (a tank top underneath fixed that, of course).
This is a comfortable shirt! My office gets pretty chilly, and the shirt was actually much warmer than I expected for the weight. I have no idea if the other shirt styles are as thin (I suspect they are), but it's actually well suited to the delicacy of the designs printed on them. These aren't rough-and-tumble work shirts here, and they also aren't cheap (then again, I'm generally a $5/3-pack Hanes undershirt kind of girl, so what do I know?). But then again, you're getting a whole lot more than a production-line commodity.
Check 'em out, and take the time to read the backstory throughout the site—this is a great example of a commercial enterprise that effectively marries sustainability with commerce, and produces quality products to boot.
April 23, 2007
Earth Day has come and gone—ours was marked by a massive spring cleaning, which brought many new green housecleaning discoveries. But that icon of edutainment, the Discovery Channel, celebrated differently, by airing a marathon of their new series, Planet Earth. If your officemates are more interested in discussing the Sopranos over the bubbler every Monday, you might not realize that this documentary series is one of the most striking nature shows ever filmed.
Producers and their crew sometimes spent months on a given shot, creeping and hiding to capture many scenes that have never actually been recorded for broadcast. You'll meet animals you've never seen before, view arial shots that make your heartbeat skip and, hopefully, be truly moved by the interconnected nature of the plant and animal species that keep this ball breathing.
My only criticism of the series is the writing. Powerfully narrated by Sigourney Weaver, even she can't elevate the typical, often trite text to anything that comes close to matching the images on screen. That said, the focus is clearly those images: the intense blues and greens and fiery oranges; the textures of sand, sea and scales; the bizarre and yet familiar behavior of species we may never have seen before. I can't even imagine what this program looks like viewed on HDTV.
The final episode, featuring the filmmakers' story, will air this Sunday, April 29. But Discovery will most likely air reruns, and you can purchase the entire series on DVD.
March 13, 2007
Children are sponges, aren't they? Izz and her older cousin, Dez, are no exceptions. A couple of wacky kids with some wacky friends and some wacky family members, Izz and Dez appear in monthly online episodes, their own blog and some interactive learning games aimed at the tween set. Through it all, they discover what it means to be green and how kids can make an impact on the world around them.
The Greens has some great things going for it, not least of which is the braintrust behind it. Created by WGBH (close to my heart, as a Boston girl born and raised), the entire thing started with—not surprisingly—TED. TED (Technology, Entertainment and Design) is an annual smarty-pants conference in which rich, left-leaning movers and shakers come up with crazy ideas to make the world a better place. Last year, photographer Ed Burtynsky won a wish from the TED community and The Greens were born.Although the show is quite funny and graphically very engaging, it has some growing and stretching to do. Writing about the environment is tough, even when you're aiming at grown-ups. Making this stuff understandable and attractive to young kids is even tougher. The Greens cleverly rely on plenty of sarcasm and pre-teen angst to earn street cred among their target audience but the incorporation of the actual green stuff can be a little dry. "Ask Hector," a bit in which Izz's buddy advises us on how to save water in just ten words, falls a little flat (it is essentially a list of ten questions with yes or no answers). Contrast that against the engaging interactive quiz game and you can see where the site's strengths and weaknesses lie.
That said, I'm not a kid anymore (I've been told immaturity doesn't count). The little monsters will ultimately be the ones to determine if The Greens are a success or not. And I hope they do; as the group discussed at this year's TED conference, one of the best ways to get mom and dad to change their ways is to convince the kids to do it first (just think about how persistent kids are at getting what they want). If all goes according to plan, each monthly episode of The Greens will continue to make green living fun for kids and their grown-ups.
February 23, 2007
Small Failures is honored to be chosen as one of Treehugger's green blogs of the week! We're certainly in good company, and it's great to get the nod from one of the leading online green magazines. Check out the other mentions as well:
December 04, 2006
Do you have a Sun Fat? How about an El Chico #4? These are just a couple of the neighborhood markets we've been frequenting recently as we try to wean ourselves from the expense that is Rainbow Grocery and the chain that is Trader Joe's.
Don't get me wrong—I love TJ's, especially their seemingly unlimited house brand selection and the fact that their staff is always—and I mean always—friendly and helpful. And I love Rainbow's selection of cheeses and craft beers. But not only do I have to drive to either of these places if I want to buy more than one bag of groceries, Rainbow is frighteningly expensive and TJ's ships their products all over the country to a rather gas-guzzling degree.
So in an effort to stay local, we went exploring. My 'hood really is just that—corner liquor stores every two blocks (one of which brilliantly blasts classical music at night to keep the thugs from hanging on their corner), dollar stores, about a dozen bars in a ten-block radius, gang members every now and then, dirty streets.
But it is also a thriving neighborhood—one of the few places in the city where families and immigrants (mostly Mexican) can afford to live. A tiny little park was just completely overhauled, and there are mom-and-pop shops everywhere. These are the places that often have more to offer than meets the eye.
These stores don't look like much from the outside. They might be in older buildings, or lack the branding of an Ikea or Starbucks. Most of them have signs that aren't in English, so unless you either know about them already or are willing to poke your head inside and get a strange look or two, you might never even notice them. But shopping at these stores reduce your environmental footprint, keep your money in the local economy, and often encourage a tighter community overall.
Some of our favorites are:
El Chico #4: A Mexican grocery that has a great selection of really good-looking produce, sundries and meats. They are always friendly and the store is always clean. The best part? I can walk out weighed down with two full bags of groceries for less than $10.
Sun Fat Seafood Company: I don't eat meat, but the ol' man does. And in his effort to cut down on red meat, he discovered this gem after searching high and low for a fish market worth frequenting. I generally don't like the smell of fish, but this place is incredible: immaculate, odor-free, well-stocked and cheap. Even I thought the fish looked appetizing, and the ol' man reports that it tastes "really good."
Philz Coffee: I've taken a break from Philz because his Turkish coffee is so intense I can only take it in small doses. But holy crap, is it good! He hand brews every cup from any of a dozen or more different hand-roasted blends.
Maybe I'm lucky that I live in el barrio because it puts me within walking distance of so many incredible family-owned businesses. But no matter where you are you likely have some, too. And the only way you'll ever discover them is if you leave your car at home, your expectations and hesitations aside, and take a walk around the 'hood.
December 02, 2006
It’s been getting mighty wintery around here lately, at least by San Francisco standards, so last night I figured to make myself a comforting bowl of macaroni and cheese. Lately I’ve been trying to master the art of Mac ‘n’ Cheese but that cheesy, creamy phenomenally addictive quality keeps eluding me. With my recent failures, small though they may be, still lingering, I opted instead for the box of Safeway “O” Organic White Cheddar Macaroni and Cheese that had been tucked away for weeks in my kitchen cabinet.
I was leary as I eyed the box, wondering just how much cheesy goodness could really lie within. Would this grocery giant, whom I generally dislike for being one of the most inefficient, un-customer friendly chains I have ever experienced, really be able to pull off organic?
I even went so far as to rummage through my fridge to see what I had for Mac ‘n’ Cheese-worthy cheese. Nothing. The box it would be. After going through the typical Kraftesque motions, I sat down with what appeared to be a quite normal bowl of that most perfect of comfort foods. And to my surprise, it was halfway decent. Nothing spectacular, mind you, but what cardboard box full of powdered cheese ever is?
Packaging: Standard cardboard box with envelope of powdered cheese, apparently not made from recycled materials. Not too surprising, as the O brand is focused on health, not sustainability or eco-friendliness. It carries the USDA Organic label. As with most foods, the actual food fills up only 1/3 of the entire package. C-
Preparation: The same as any boxed mac ‘n’ cheese. For once, the boiling time (8-10 min.) is actually accurate. Add in a little butter, milk, and the accompanying powdered cheese and you’ve got yourself a dinner. The only problem was that the cheese wasn’t easy to melt (even though I left it simmering while I added everything in).B
Appearance: Looks darn good, if you ask me. White cheddar cheese means there’s not much color, but it looks creamy and cheesy. B+Taste: It tastes like quality cheese, as opposed to fake powdery stuff. It doesn’t have that addictive quality (I prefer Annie’s for that), but it also doesn’t feel too heavy. Because the cheese didn’t melt very well, the result was a somewhat uneven cheesiness. Ah well, you can’t ‘em all. B+
The upshot: A great alternative to any of the conventional brands. I have yet to try Annie’s Organic Shells & White Cheddar, but my local Safeway charges almost a dollar more for it. That’s one of the advantages of the house labeled products. If Safeway were my only shopping option, I’d likely keep a couple of boxes on hand for emergency dinners. But for now, I’ll stick to scratch until I master the Mac ‘n’ Cheese. B |
To celebrate the release of No Straight Roads, we're giving away a few exclusive vinyl sets and soundtracks!
Realm Royale is the latest battle royale game to storm computer systems around the world, and players who are diving in have been less than excited to find the game capped out at 150FPS. The good news is you can easily uncap the FPS in Realm Royale. So, here’s what you need to know to uncap FPS in Realm Royale.
How to Uncap FPS in Realm Royale
Before we get started, we do want to point out that uncapping your FPS in Realm Royale will require you to mess around in your game files some. If you aren’t comfortable doing this, then please do not try this. However, the process is actually pretty simple, so just follow our instructions if you feel comfortable messing around with your game files.
Find Your Game Files
First off, head to the install location of your Realm Royale game files. Depending on where you installed it to, this could be any kind of path like C:\Program Files (x86)\Steam\steamapps\common\Realm Royale.
Once here, locate the RealmGame folder and open it up.
Now, find the Config folder and open it up.
Edit the DefaultEngine File
Now that you’re in the Config folder, locate a file called DefaultEngine and open it up in your computer’s Notepad application. There’s going to be quite a bit of information in this document, so press Control F on your keyboard and then search bSmoothFrameRate to find the option easily. Once you’ve found it, locate the option at the end and chance it from TRUE to FALSE. It should now look like this:
bSmoothFrameRate=FALSE
Now that you’ve done that, save the document and exit Notepad. Close out all the folders and then launch the game with an uncapped FPS. Will Realm Royale come to the PS4 or Nintendo Switch? Find out by checking out our article. You can also check out our guide to all the classes and abilities in Realm Royale for more information about the game.
We’ll continue to provide strategy content for Realm Royale as the weeks go by, so make sure you check back often to see the latest information, patch notes and more. |
Justification:Acacia bifaria is a small shrub with a restricted distribution in mallee of Western Australia between Ravensthorpe and Fitzgerald River. This shrub is only known from approximately six localities and mostly distributed outside protected areas in a highly fragmented habitat due to clearing for agriculture. The extent of occurrence warrants this species a listing of Endangered (EOO ~3,700 km²). Changes in fire regimes, increased salinity, mining activities and grazing pressure are threatening processes to this habitat. Furthermore, despite some populations known from the Fitzgerald National Park, there are concerns over the devastating effects that the pathogen Phytophthora cinnamomi might have on the vegetation of the area if the spread of this disease is not contained. If the current management measures to contain the spread are not successful there is a high risk that some subpopulations will become extinct. It is recommended that monitoring of the habitat status, threats and pathogen are continued.
Acacia bifaria is endemic to Australia, only known from Ravensthorpe to the Fitzgerald River (c. 30 km east of Jerramungup) in southwestern Western Australia. Recent surveys conducted around Wellstead found the species in in the area (Ecologia Environment 2008).
There are no direct threats to the species, however, according to the Biodiversity Assessment carried out for the Australian Natural Resources Atlas, the condition of the Esperance Plains region, where this species occurs, is fair to poor with a declining trend generally. Threatening processes to the area include vegetation clearing and fragmentation for agriculture, hydrological changes and salinity, feral predators and herbivores, grazing by stock and weeds. Many communities and species are localized in occurrence and vulnerable to fire events. In the Esperance region (ESP1 Fitzgerald subregion) approximately half of it has been cleared of native vegetation and agriculturally productive landscapes are now almost completely cleared (Comer et al. 2001). Despite the fact that this species is not susceptible to root-rot fungus (Groves et al. 2009) Phytophthera is changing the composition of coastal heath and scrub communities (Australian Natural Resources Atlas 2009). Most importantly, recent news reports warn that dieback root-disease is posed to tear through the Fitzgerald National Park, despite efforts from the Project Dieback to contain the spread of the pathogen (Bennet 2010). Dr. Chris Dunne from the Dieback Working Group (2009) reported that ‘The research indicates that the impacts of the disease along the south-coast are likely to be even more significant than in the Jarrah forest where the disease was first observed to cause mass collapse of forest sites. Extreme weather events, such as summer rainfall linked to northern cyclone activities, can lead to a significant spread of dieback and a mass collapse in these native vegetation sites”. Some populations are also threatened by mining activities, the species is found in proposed site for an open pit Magnetite mine (Ecologia Environment 2008) and in exiting mines in Elverdton-Desmond area (Department of Industry and Resurces; Department of Mines and Petroleum).
Although most collections do not appear to be within protected areas, this species is known to occur within the Fitzgerald River National Park. It is listed as 2KC- in Briggs and Leigh (1995) a poorly known taxon with a geographic range less than 100 km2 that is known to occur within a reserved but the population size is not known. It is also listed as Priority 3 in Smith (2010) taxa which are known from several populations, at least some of which are not believed to be under immediate threat. |
Remove all your fish from your tank by scooping them out of the water with your net. Place the fish in your backup aquarium, where they can safely reside while you clean the hard water deposits off your primary aquarium.
I am also having trouble finding fish that will not eat the plants but dont mind a high ph. so far i am going to get either 1 or 2 albino bristlenoses but beyond that i am not sure(my tank is 30 gallons 36" long). With my hard water and high ph i have thought about something from lake victoria but alot of those fish get to big and like to dig. i also have thought about tanganyika but i do not want shell dwellers and dont know what else i could get.
Aquarium Water That Is Too Hard - Petcha
One of the paradoxes in freshwater fishkeeping is thatwhile most fish naturally from soft water environments will thrive inhard water aquaria, the reverse is almost universally not true. Tetras,Barbs, Gouramis, catfish and Angelfish are allexamples of originally soft water fish that are routinely andsuccessfully kept in hard water community tanks. But Livebearers,Central American cichlids and Rift Valley cichlids almost never adaptto soft and acidic water conditions. In other words, if all you want isa mixed community tank, then hard and alkaline water will allow you tomix Platies, Neons and without problems.
Aquarium Water Hardness | Tropical Fish Success
As a rule, the popular South American tetrastend to tolerate rather than thrive in hard water. Some, like Neons,cardinals, and Glowlights, suffer somewhat, and their mortality inhard, alkaline water can be very high. Nonetheless, a few tetras doinhabit hard water streams and rivers, and these make excellent choicesfor the aquarist with a hard water aquarium. One of the best is thex-ray tetra, , a pretty, peaceful tetra thatadds colour and movement to any community of small fishes. It isn'ta fin-nipper, and so can be trusted with things like guppies, and isbig enough that it isn't at risk of being eaten by things likehalfbeaks or dwarf cichlids. Another fine choice for the community tankis the blind cave tetra, . Because this fishinhabits streams in limestone caves, it is perfectly adapted to hard,alkaline water. It is, of course, a wonderful oddball fish, and despitehaving no eyes it has an uncanny way of navigating and finding foodvery effectively; a splendid fish for the aquarist after somethingdifferent.
Neither did I when I got started with my first fish tank
Removing Hard Water Stains from an Aquarium - YouTube
Eastern Rainbowfish MelanotaeniasplendidaThis is one of the many Australian species that are traded from time totime. They are fairly large, getting to about 15 cm/6 inches, and havesilvery bodies covered with red and blue speckles; their fins aremarked with red, green and blue. These fish are hardy and easy to keep,but given their size, will need plenty of swimming space,realistically, a tank at least 120 cm/48 inches long. Waterchemistry: 10-20 degrees dH, pH 7.0-8.0.Temperature: 22-28 C/72-82 F. Diet:Flake, frozen foods, small live foods.
Beautiful colorful fish for hard water aquarium
I have a fish tank with two goldfish and a red eared slider turtle in it. I have some hard water/foggy stains on part of the glass that is not under water now. How do I clean the glass without killing the turtle and his pets? The tank is 30 gallons, and there is about 25-27 gallons of water in it. |
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Hostess survives liquidation for another day
Company, union agree to try and reach resolution
By Candice Choi Associated Press
Posted:
11/19/2012 10:56:01 PM MST
Updated:
11/19/2012 10:57:12 PM MST
WHITE PLAINS, N.Y. -- Twinkies will live to see another day.
Hostess Brands Inc. and its second largest union agreed on Monday to try to resolve their differences after a bankruptcy court judge noted that the parties hadn't gone through the critical step of private mediation. That means the maker of the spongy cake with the mysterious cream filling won't go out of business yet.
The news comes after the maker of Ho Ho's, Ding Dongs and Wonder Bread last week moved to liquidate and sell off its assets in bankruptcy court. Hostess cited a crippling strike started on Nov. 9 by the Bakery, Confectionery, Tobacco Workers and Grain Millers International Union, which represents about 30 percent of Hostess workers.
"Many people, myself included, have serious questions as to the logic behind this strike," said Judge Robert Drain, who heard the case in the U.S. Bankruptcy Court in the Southern District of New York in White Plains, N.Y. "Not to have gone through that step leaves a huge question mark in this case."
The mediation talks are set to take place Tuesday, with the liquidation hearing set to resume on Wednesday if an agreement isn't reached. Jeff Freund, an attorney for the bakers union, said any guess as to how the talks will go would be "purely speculative."
In an interview following the hearing, Hostess CEO Gregory Rayburn said that there is enormous financial pressure to come to an agreement with the union by the end of the day Tuesday.
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He noted that it's costing Hostess about $1 million a day in payroll costs alone to stay alive, with the money mostly going toward management to unwind the company. About 18,000 workers were sent home Friday after the company shuttered its 33 plants, meaning no sales are being generated.
"We didn't think we had a runway, but the judge just created a 24-hour runway," said Rayburn, who added that even if a contract agreement is reached, it's unclear whether all Hostess plants will get up and running again.
Hostess, weighed down by debt, management turmoil, rising labor costs and the changing tastes of Americans, decided on Friday that it no longer could make it through a conventional Chapter 11 bankruptcy restructuring. Instead, the company, which is based in Irving, Texas, asked the court for permission to sell its assets and wind down its business.
The company, which is in its second bankruptcy in less than a decade, had said that it was saddled with costs related to its unionized workforce. It brought on Rayburn as a restructuring expert in part to renegotiate its contract with labor unions.
Hostess, which had been contributing $100 million a year in pension costs for workers, offered workers a new contract that would've slashed that to $25 million a year, in addition to wage cuts and a 17 percent reduction in health benefits. The baker's union rejected the offer and decided to strike.
By that time, Hostess had reached a contract agreement with its largest union, the International Brotherhood of Teamsters, which urged the bakers union to hold a secret ballot on whether to continue striking. Although many workers in the bakers union decided to cross picket lines this week, Hostess said it wasn't enough to keep operations at normal levels.
Rayburn said that Hostess was already operating on razor thin margins and that the strike was the final blow. The bakers union said the company's demise was the result of mismanagement, not the strike.
Boulder is pretty good at producing rock bands, and by "rock," we mean the in-your-face, guitar-heavy, leather-clad variety — you know, the good kind. For a prime example, look no farther than BANDITS. Full Story |
In April of 2017, Shane Goldmacher reported in Politico noted that Justice Anthony Kennedy and President Trump had a conversation after Trump’s first speech to Congress that was picked up by boom microphones.
Here is the conversation they had, as quoted in Politico:
“Say hello to your boy,” Trump said, “Special guy.” “Your kids have been very nice to him,” Kennedy replied. “Well,” Trump said, “they love him, and they love him in New York.”
Kennedy’s son Gregory Kennedy worked at NASA in the early days of the Trump administration, as one of the political appointees the president chose to serve as his eyes and ears at major federal agencies. (That group of appointees was described by ProPublica in March 2017 and revised in August of the same year. ProPublica reported that Gregory Kennedy was appointed January 20, Inauguration Day.)
Gregory Kennedy attended Stanford law School with Trump technology advisor Peter Thiel, and his company, Disruptive Technology Advisors, has worked with Thiel’s company, Palantir.
Justin Kennedy is an associate of Donald Trump, Jr., through New York real estate. He has worked for Goldman Sachs and Deutsche Bank. Financial Times reported in August 2017:
“Justin Kennedy, a trader who arrived from Goldman to become one of Mr Trump’s most trusted associates over a 12-year spell at Deutsche, is the son of a Supreme Court justice.”
It seems that there are a number of family-financial connections between the Trump and Kennedy families. Perhaps Justice Kennedy should have recused himself from Supreme Court cases involving the Trump administration.
Tuesday Justice Kennedy wrote a concurrence for the Supreme Court’s 5-4 decision to uphold Trump’s travel ban on people from seven countries (Iran, Libya, North Korea, Somalia, Syria, Venezuela, and Yemen). Wednesday, he announced that he will retire from the Court at the end of July.
Three members of the Trump transition team - Michael, Flynn, Steve Bannon, and Jared Kushner - met January 5, 2017 with Jordan’s King Abdullah II at the Four Seasons Hotel in Manhattan. At the time, soon-to-be national Security Advisor Flynn was promoting a $400 billion deal to build nuclear reactors in the Middle East, including Jordan.
According to Buzzfeed, they greeted the king at the hotel and then took off with him in a fleet of SUVs for an undisclosed location.
This part of the article is particularly interesting:
“People close to the three Trump advisers say that the nuclear deal was not discussed. But a federal official with access to a document created by a law enforcement agency about the meeting said that the nuclear proposal, known as the Marshall Plan, was one of the topics the group talked about.”
This means that the group was under surveillance by U.S. law enforcement at the time of the meeting.
The plan included using a Russian firm currently under U.S. sanctions to run security at the plants. |
Intestinal Surgery for Crohn's Disease: Role of Preoperative Therapy in Postoperative Outcome.
Patients affected by Crohn's disease (CD) require lifelong medical therapy, but they can also often require abdominal surgery. The effect of CD therapy on postoperative course is still unclear. The aim of this study was to evaluate the effect of preoperative medical therapy on the outcome of intestinal surgery in these patients. Data from a consecutive series of 167 patients with CD operated on at the University of Padova Hospital from 2000 to 2013 were retrieved. Data of preoperative therapy during the 6 months before surgery were available for 146 patients who were enrolled in this retrospective study. Clinical data and surgical details were retrieved and postoperative complications and reoperation were considered outcome measures. Univariate and multivariate analysis were performed. No significant difference was observed between patients without data about their preoperative therapy and those with them. Eight patients underwent reoperation in the first 30 postoperative days: two of them for anastomotic leak, three for bleeding, one for obstruction and two for abdominal wound dehiscence. At multivariate analysis, preoperative adalimumab and budesonide resulted to be an independent predictor of reoperation (OR = 7.67 (95% CI = 1.49-39.20), p = 0.01 and OR = 6.7749 (95% CI = 0.98-46.48), p = 0.05, respectively). At multivariate analysis neither pharmacological nor clinical variables resulted to predict anastomotic leak. In our series, adalimumab seemed to be associated to early reoperation after intestinal surgery. This may be due to a worst disease severity in patients who needed surgery in spite of biological therapy. Preoperative tapering of budesonide dose seems a safe option before elective abdominal surgery for CD. |
Joe Root denies England Test squad has a drinking culture – video
Play Video
0:46
England Test captain, Joe Root, says there isn't a drinking culture within his side before the forthcoming Ashes series against Australia. It comes after vice-captain Ben Stokes was arrested last month after an incident on a night out and released without charge. Stokes remains suspended and will not fly out with squad |
Top laminated graphene electrode in a semitransparent polymer solar cell by simultaneous thermal annealing/releasing method.
In this article, we demonstrate a semitransparent inverted-type polymer solar cell using a top laminated graphene electrode without damaging the underlying organic photoactive layer. The lamination process involves the simultaneous thermal releasing deposition of the graphene top electrode during thermal annealing of the photoactive layer. The resulting semitransparent polymer solar cell exhibits a promising power conversion efficiency of approximately 76% of that of the standard opaque device using an Ag metal electrode. The asymmetric photovoltaic performances of the semitransparent solar cell while illuminated from two respective sides were further analyzed using optical simulation and photocarrier recombination measurement. The devices consisting of the top laminated transparent graphene electrode enable the feasible roll-to-roll manufacturing of low-cost semitransparent polymer solar cells and can be utilized in new applications such as power-generated windows or multijunction or bifacial photovoltaic devices. |
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ScalaTest 2.0 Release Notes
ScalaTest 2.0 is a major upgrade to ScalaTest, the culmination of over two years of effort. Although it includes many enhancements, we kept a close eye on compatibility with existing ScalaTest 1.x code. We also tried hard to preserve what people liked about ScalaTest 1.x: that it is simple, the code is clean and clear, it's fully documented, and because of very thorough testing, it “just works.”
For information on how to include ScalaTest in your project, see the download page.
Highlights
ScalaTest 2.0 is such a big upgrade that you could easily get lost all in the details of what's new. This section gives the main highlights subdivided into general categories, with links to more detail. To get a quick idea of what's new in ScalaTest 2.0, scan through this section.
Equality enhancements
Suite enhancements
Added an Outcome result type to withFixture .
result type to . Added a Status result type to Suite 's run methods, and used Status to ensure BeforeAndAfterAll 's afterAll method is executed after any parallel execution completes.
result type to 's methods, and used to ensure 's method is executed after any parallel execution completes. Refactored Suite 's run methods to take an Args , to make overriding nicer.
's methods to take an , to make overriding nicer. Added markup to style traits to include markup text for specifications.
to style traits to include markup text for specifications. Added note and alert to stye traits for sending status notifications from tests.
and to stye traits for sending status notifications from tests. Added Sequential and Stepwise (to pre-existing Suites ) combinators for suite composition.
and (to pre-existing ) combinators for suite composition. Added support for they (in addition to it ) to FunSpec and FlatSpec .
(in addition to ) to and . Added ability to tag all tests in a suite class by annotating the class with a tag annotation. For example, can ignore all tests in a suite class with @Ignore .
. Added DynaTags and a dynaTags field to the primary constructor of class Filter to enable the dynamic tagging of tests. Dynamic tagging facilitates features such as test name wildcards and rerunning previously failed tests; It enables selection of tests even in nested suites that can't be instantiated directly.
and a field to the primary constructor of class to enable the dynamic tagging of tests. Dynamic tagging facilitates features such as test name wildcards and rerunning previously failed tests; It enables selection of tests even in nested suites that can't be instantiated directly. Added the suiteId lifecycle method to trait Suite . This new lifecycle method is intended to provide a unique ID for each suite that executes in a suite of tests, so that tests can be dynamically tagged. (A dynamic tag identifies tests by suiteId and testName .)
lifecycle method to trait . This new lifecycle method is intended to provide a unique ID for each suite that executes in a suite of tests, so that tests can be dynamically tagged. (A dynamic tag identifies tests by and .) Added a rerunner lifecycle method to Suite , which provides an optional, fully qualified name of a suite (with a public, no-arg constructor) that can be used create to rerun its tests. If class has a public, no-arg constructor, then that class's fully qualified name can be returned from rerunner . If it does not have a public, no-arg constructor, but rather is created as a nested suite of a class that does have a public, no-arg constructor, then the nested class can return from rerunner the fully qualified name of that outer, nesting class. To rerun a test in the nested class, ScalaTest can create the nesting class via its public, no-arg constructor, and run it. The nesting class will create the actual class in which the test resides, and run it as a nested suite, thereby rerunning the test.
lifecycle method to , which provides an optional, fully qualified name of a suite (with a public, no-arg constructor) that can be used create to rerun its tests. If class has a public, no-arg constructor, then that class's fully qualified name can be returned from . If it does not have a public, no-arg constructor, but rather is created as a nested suite of a class that does have a public, no-arg constructor, then the nested class can return from the fully qualified name of that outer, nesting class. To rerun a test in the nested class, ScalaTest can create the nesting class via its public, no-arg constructor, and run it. The nesting class will create the actual class in which the test resides, and run it as a nested suite, thereby rerunning the test. Added a boolean excludeNestedSuites field to the primary constructor of class Filter . This field supports rerunning selected (such as previously failed) tests.
field to the primary constructor of class . This field supports rerunning selected (such as previously failed) tests. Added traits Spec and fixture.Spec to serve as the new style trait in which tests are methods, and deprecated the use of Suite as a style trait.
and to serve as the new style trait in which tests are methods, and deprecated the use of as a style trait. Added a @DoNotDiscover annotation that prevents discovery of an otherwise discoverable Suite class.
SuiteMixin enhancements
Added trait SuiteMixin to serve as the new base class for stackable traits that can be mixed into Suite , and deprecated trait AbstractSuite .
to serve as the new base class for stackable traits that can be mixed into , and deprecated trait . Added TestData trait, made NoArgTest and OneArgTest implement it, and added trait BeforeAndAfterEachTestData to faciliate using the test name, text, scopes, and tags, as well as the config map, in withFixture , beforeEach , and afterEach methods.
trait, made and implement it, and added trait to faciliate using the test name, text, scopes, and tags, as well as the config map, in , , and methods. Added BeforeAndAfterAllConfigMap to faciliate using the config map in beforeAll and afterAll methods.
to faciliate using the config map in and methods. Changed the behavior of BeforeAndAfterAll so that it only calls beforeAll and afterAll in the outer instance of a OneInstancePerTest or ParallelTestExecution .
so that it only calls and in the outer instance of a or . Enhanced BeforeAndAfterAll and BeforeAndAfterAllConfigMap to take expectedTestCount into consideration when deciding whether to invoke beforeAll and afterAll .
and to take into consideration when deciding whether to invoke and . Modified OneInstancePerTest so that it calls super.runTests which emits events for scopes (such as describe clauses in FunSpec ).
so that it calls which emits events for scopes (such as clauses in ). Similarly, modified ParallelTestExecution so that it calls super.runTests which emits events for scopes (such as describe clauses in FunSpec ).
so that it calls which emits events for scopes (such as clauses in ). Added a Retries trait (and related Retryable tag) and a Catcher class to help deal with flickers: tests that usually pass but occasionally fail.
Assertions enhancements
Added the ability to cancel a test. Added assume and cancel methods to Assertions , and added a cancelAfter method to Timeouts .
and methods to , and added a method to . Reimplemented assert and assume as macros that produce descriptive error messages in Assertions .
and as macros that produce descriptive error messages in . Added Inspectors ( forAll , forEvery , forAtLeast , forAtMost , forBetween , forExactly ) to enable assertions about collections, including nested collections.
( , , , , , ) to enable assertions about collections, including nested collections. Added LoneElement to assert against single-element collections.
to assert against single-element collections. Added TryValues to facilitate assertions about Try values.
to facilitate assertions about values. Added AsyncAssertions to org.scalatest.concurrent .
to . Added ScalaFutures to help write tests involving Scala futures.
to help write tests involving Scala futures. Added Checkpoints , which allows you to accumulate and report multiple assertions in a single test.
Matchers enhancements
Runner enhancements
For a table of all the available options, see the main Scaladoc documentation for Runner .
. Added support for reminders, a summary of failed and/or canceled tests that can be optionally printed out at the end of a run in string (stdout, stderr, file) reporters. This obviates the need to scroll backwards in search of details about failed and/or canceled tests in console output, and also ensures that such details won't have scrolled off the top and out of existence.
Enhanced -s to take a glob in addition to a complete, fully-qualified suite class name.
to take a glob in addition to a complete, fully-qualified suite class name. Added slowpoke notifications, which emit AlertProvided events periodically listing tests that have been running longer than a specified time limit. (-W)
events periodically listing tests that have been running longer than a specified time limit. (-W) Added ability to memorize and rerun failed and canceled tests. (-M and -A)
Added to Runner a way to specify tests to run by full or partial ("wildcard") name ( -z ).
a way to specify tests to run by full or partial ("wildcard") name ( ). Enabled on-the-fly sorting of events (with a timeout) during parallel runs ( -PS ).
). Added unformatted mode to stdout (-oU), stderr ( -eU ), and file reporters ( -fU ) for helping debug problematic parallel test runs.
), and file reporters ( ) for helping debug problematic parallel test runs. Added a socket reporter (-k), which serializes events to a socket. This facilitates running tests remotely, such as with sbt's forking feature.
Added a -i command line argument to Runner to provide a way to specify a suite by suite ID. This complements the -s command, which allows you to identify a suite by fully qualified name. The -i command was added primarily to allow IDEs and other tools to rerun failed (or otherwise selected) tests.
command line argument to to provide a way to specify a suite by suite ID. This complements the command, which allows you to identify a suite by fully qualified name. The command was added primarily to allow IDEs and other tools to rerun failed (or otherwise selected) tests. Added a -t to Runner , a way to specify a specific test name. A -t clauses may follow -s or -i , or be standalone. All -t 's immediately following a -s or -i will be considered tests of the suite specified by that -s or -i . If -t <test name> appears standalone, Runner will execute any tests with matching names on any suite discovered in the runpath.
to , a way to specify a specific test name. A clauses may follow or , or be standalone. All 's immediately following a or will be considered tests of the suite specified by that or . If appears standalone, will execute any tests with matching names on any suite discovered in the runpath. Added a -z argument to Runner , a means to specify test names via a wildcard: any test whose string name includes the string specified with -z will be selected. -z clauses may follow -s or -i clauses, or be standalone. All -z 's immediately following a -s or -i will be considered wildcards selecting tests of the suite by that -s or -i . If -z <test name wildcard> appears standalone, Runner will execute any tests with matching names on any suite discovered in the runpath.
argument to , a means to specify test names via a wildcard: any test whose string name includes the string specified with will be selected. clauses may follow or clauses, or be standalone. All 's immediately following a or will be considered wildcards selecting tests of the suite by that or . If appears standalone, will execute any tests with matching names on any suite discovered in the runpath. Added the ability to sort events on-the-fly when suites are run in parallel, with a tunable timeout (that defaults to 15 seconds) if a suite takes to long to complete. This balances the desire to have sorted output with the desire to see what's happening while you are watching. On-the-fly sorting is disabled by default, and can be enabled with -PS argument to Runner .
argument to . Added the ability to specify a timeout for sorting during parallel runs. The -T parameter takes a number of seconds, which is used for test sorting. The value specified with -T plus one second is used for suite sorting.
plus one second is used for suite sorting. Added the ability to sort events locally when tests (i.e., not suites) are run in parallel via ParallelTestExecution , with a timeout if a test takes too long. Added sortingTimeout to ParallelTestExecution , the default of which is to use the timeout specified to Runner via -T (or 15 seconds if no -T given), but you can override the method. Added trait DistributedTestSorter to support this feature, and a field holding a DistributedTestSorter in Args
Enhancements for better tools integration
Added new tags CPU , Disk , Network , and reporting these as sbt's built-in resource tags, Tags.CPU , Tags.Disk , and Tags.Network .
, , , and reporting these as sbt's built-in resource tags, , , and . Added a location API for better integration with tools, especially IDEs. The location API consists of a sealed family of classes and objects, consisting of abstract base class Location , three case subclasses LineInFile , TopOfMethod , and TopOfClass , and singleton object SeeStackDepthException .
, three case subclasses , , and , and singleton object . Added a Finders annotation that specifies one or more Finders that can be used to determine selected tests from an AST in IDEs.
annotation that specifies one or more that can be used to determine selected tests from an AST in IDEs. Enhanced the ScalaTest Maven Plugin so that all of the new Runner features are accessible to Maven users.
features are accessible to Maven users. Enhanced the ScalaTest Ant Task so that all of the new Runner features are accessible to Ant users, including Gradle and Buildr users who often go through the Ant task.
features are accessible to Ant users, including Gradle and Buildr users who often go through the Ant task. Created the ScalaTest Exclipse Plugin, which is a standard part of the Scala IDE Ecosystem.
Defined the New Framework API, and integrated it both with sbt (i.e., we contributed this to sbt) and ScalaTest. The New Framework API makes all features of Runner accessible to the users of sbt, which was not possible with the original Framework API. Support for the new Framework API was released as part of sbt 0.13.
Event model enhancements
Added DiscoveryStarting and DiscoveryCompleted events, and enhanced the GUI reporter to use these events to show a spinning icon during discovery.
and events, and enhanced the GUI reporter to use these events to show a spinning icon during discovery. Added ScopeOpened and ScopeClosed events to indicate scopes, such as the scope of a describe clause in a FunSpec . Previously a “scope opened” event was indiciated via an InfoProvided events with IndentedText .
and events to indicate scopes, such as the scope of a clause in a . Previously a “scope opened” event was indiciated via an events with . Added a MarkupProvided event to indicate some markup text has been provided.
event to indicate some markup text has been provided. Added a testText field to all test events ( TestStarting , TestIgnored , TestPending , TestCanceled , TestFailed , and TestSucceeded ), primarily for integration with IntelliJ IDEA. The “test text” is either the complete test name or a suffix of it. In a FunSpec , for example, the test text will be the string passed to the it method, whereas the full test name will be the test text prefixed by the strings passed to enclosing describe method calls.
field to all test events ( , , , , , and ), primarily for integration with IntelliJ IDEA. The “test text” is either the complete test name or a suffix of it. In a , for example, the test text will be the string passed to the method, whereas the full test name will be the test text prefixed by the strings passed to enclosing method calls. Added location , an Option[Location] field, to class Event .
, an field, to class . Added a suiteId to relevant events: TestStarting , TestSucceeded , TestFailed , TestFailed , TestPending , TestCanceled , SuiteStarting , SuiteCompleted , SuiteAborted . This enables tests run previously to be dynamically tagged in future runs (because a dynamic tag requires both the testName and suiteId ).
to relevant events: , , , , , , , , . This enables tests run previously to be dynamically tagged in future runs (because a dynamic tag requires both the and ). Added a recordedEvents field to test completion events: TestPending , TestSucceeded , TestFailed , and TestCanceled . Added sealed trait RecordedEvent , which extends Event and has two subtraits: InfoProvided and MarkupProvided . Prior to 2.0, InfoProvided events were recorded during tests and played back after, so that they could appear after the test text in the standard out reporter, and in a color that matched that of the test text. The color of the test text (green if passed, red if failed, yellow if pending, etc.) could not be known until after the test had completed. By sending recorded events along with the test completion event, rather than playing them back afterwords, it is easier for Reporter s to figure out when the last event for a test has been received.
Miscellaneous enhancements
Added the ScalaTest Selenium DSL.
Added an HTML reporter. Here's an example HTML report.
To make thread dumps more clear, gave useful names to ScalaTest threads: The main thread is now ScalaTest-main . The run thread is ScalaTest-run . The dispatcher thread is ScalaTest-dispatcher . Thread-pool threads for parallel execution are ScalaTest-N . And main or thread-pool threads running test suites are renamed to ScalaTest-running-<name of suite> , then changed back again once the suite has completed.
. The run thread is . The dispatcher thread is . Thread-pool threads for parallel execution are . And main or thread-pool threads running test suites are renamed to , then changed back again once the suite has completed. Added trait NoArg to support a relatively rare use case motivated by Akka's TestKit.
to support a relatively rare use case motivated by Akka's TestKit. Added Slow tag for marking slow tests.
tag for marking slow tests. Added trait TimesOnInt , which allows you to repeatedly execute a block of code an integer number of times via syntax such as, 3 times println .
, which allows you to repeatedly execute a block of code an integer number of times via syntax such as, . Added Or and Every to ScalaUtils, allowing you to represent errors in production code as “alternate return values” (like Either) and to optionally accumulate errors.
Potential breakages
Although we have worked hard to ensure the vast majority of ScalaTest 1.x code to compile under 2.0, ScalaTest 2.0 does include a few enhancements that can break existing code. To see the list, and learn how to migrate your code if affected, see the migration guide.
New deprecations
Deprecated the before / afterEach(TestData) methods in BeforeAndAfterEach in favor of BeforeAndAfterEachTestData .
/ methods in in favor of . Deprecated FailureOf in favor of OutcomeOf .
in favor of . Deprecated expect and expectResult in Assertions in favor of assertResult .
and in in favor of . Deprecated the use of Suite as a style trait in favor of newly added Spec .
as a style trait in favor of newly added . Deprecated the assert and assume methods whose === and !== operator return Option[String] in favor of assert and assume macros that return Boolean .
and methods whose and operator return in favor of and macros that return . Deprecated the plusOrMinus operator used with Matchers in favor of the +- symbol.
operator used with in favor of the symbol. Deprecated ShouldMatchers and MustMatchers , both members of package org.scalatest.matchers , have been deprecated in favor of Matchers , which resides in package org.scalatest . ( MustMatchers was actually already deprecated in ScalaTest 1.9.2.) For folks using ShouldMatchers , getting rid of the deprecation warning should be as simple as replacing org.scalatest.matchers.ShouldMatchers with org.scalatest.Matchers . For folks using MustMatchers , however, it will unfortnately be slightly more trouble, because the new Matchers trait only supports should not must . So you will need to search and replace your uses of must with should . MustMatchers and must will continue to work for a good long deprecation period, but eventually it will be removed to make way for must possibly coming back later to serve a different purpose. Apologies for this rather large deprecation. Update: MustMatchers was resurrected in 2.1.0 in the org.scalatest package, so there's no need anymore to change must to should . In fact, the org.scalatest.MustMatchers type alias was accidentally left undeprecated in 2.0, so where you are mixing in trait org.scalatest.matchers.MustMatchers , you can in 2.0 get rid of the deprecation warning by mixing in org.scalatest.MustMatchers instead.
and , both members of package , have been deprecated in favor of , which resides in package . ( was actually already deprecated in ScalaTest 1.9.2.) For folks using , getting rid of the deprecation warning should be as simple as replacing with . For folks using , however, it will unfortnately be slightly more trouble, because the new trait only supports not . Deprecated the beforeAll and afterAll methods of trait BeforeAndAfterAll that take a config map in favor of newly added BeforeAndAfterAllConfigMap .
and methods of trait that take a config map in favor of newly added . Deprecated given / when / then / and methods of trait GivenWhenThen in favor of capitalized forms, Given / When / Then / And , because then has been deprecated as an identifier in Scala 2.10.
/ / / methods of trait in favor of capitalized forms, / / / , because has been deprecated as an identifier in Scala 2.10. Deprecated the two previously existing apply methods on Filter , and added two new ones that take an additional suiteId parameter.
methods on , and added two new ones that take an additional parameter. Deprecated trait AbstractSuite in favor of newly added trait SuiteMixin , to serve as the new base class for stackable traits that can be mixed into Suite .
in favor of newly added trait , to serve as the new base class for stackable traits that can be mixed into . Deprecated the apply method on Distributor in favor of a newly added overloaded apply method that takes a Args . During the deprecation period, the old form will call the new form with default args. The purpose of this change was to make more information available to Distributor implementations.
Expired deprecations
Removed BeforeAndAfterEachFunctions and BeforeAndAfterAllFunctions , which had been deprecated since ScalaTest 1.6.1. If you haven't done so already, you'll need to use BeforeAndAfter instead of BeforeAndAfterEachFunctions , and BeforeAndAfterAll instead of BeforeAndAfterAllFunctions .
and , which had been deprecated since ScalaTest 1.6.1. If you haven't done so already, you'll need to use instead of , and instead of . Removed MultipleFixtureFeatureSpec , MultipleFixtureFlatSpec , MultipleFixtureFreeSpec , MultipleFixtureFunSuite , MultipleFixturePropSpec , MultipleFixtureSpec , and MultipleFixtureWordSpec , which had been deprecated since ScalaTest 1.6.1. If you haven't done so already, you'll need to mix in ConfigMapFixture to a fixture.X trait instead.
, , , , , , and , which had been deprecated since ScalaTest 1.6.1. If you haven't done so already, you'll need to mix in to a trait instead. Removed org.scalatest.SuperSuite , which had been deprecated since ScalaTest 1.5. Please use Suites instead.
, which had been deprecated since ScalaTest 1.5. Please use instead. Removed the deprecated implicit conversion in the Stopper companion object that converted a Stopper to function type () => Boolean . This implicit conversion was added when the inheritance relationship between Stopper and Function0[Boolean] was severed to make it possible for Stopper to be implemented in Java. (Severing this relationship was originally a request by the IntelliJ IDEA folks, who wanted to write integration code in Java to smooth over binary incompatibilities between different Scala versions.)
companion object that converted a to function type . This implicit conversion was added when the inheritance relationship between and was severed to make it possible for to be implemented in Java. (Severing this relationship was originally a request by the IntelliJ IDEA folks, who wanted to write integration code in Java to smooth over binary incompatibilities between different Scala versions.) Removed the implicit conversion from Reporter to Event => Unit function type in the Reporter companion objecgt, which had been deprecated since ScalaTest 1.5.
to function type in the companion objecgt, which had been deprecated since ScalaTest 1.5. Removed the implicit conversion from Rerunner to Function7 , which had been deprecated since ScalaTest 1.5.
Detailed history of changes
For historians, the detailed history page preverves relevant sections of the individual release notes for major 2.0 milestones and release candidates. For a quicker to read and more understandable overview, see the Highlights section above.
Acknowledgments
ScalaTest 2.0 is brought to you by Artima, Inc., where it is tended by Bill Venners, Chua Chee Seng, and George Berger. We would like to thank all our users for their suggestions and input, everyone who has contributed source code or reviewed our work-in-progress, and our financial sponsors (who prefer to remain unamed). Without your guidance and support, ScalaTest 2.0 would not have been possible. |
Q:
References on the physics of anyons
Anyone know some good introductory references on the physics of anyons?
A:
One of the best recent references is the 2008 RMP article by Nayak et al. Non-Abelian Anyons and Topological Quantum Computation
A somewhat less technical reference is An Anyon Primer by Sumathi Rao.
There are many others but these two are good for someone starting out.
A:
Ady Stern, Anyons and the quantum Hall effect - a pedagogical review, arXiv:0711.4697 is a gentle introduction.
|
Scarlett Johansson is making the rounds to promote her latest film, Ghost in the Shell, and naturally people are using the opportunity to ask her questions about her involvement with Avengers: Infinity War. While on MTV’s Happy Sad Confused podcast, Johansson spoke about Black Widow’s reaction to meeting the Guardians of the Galaxy:
“Somebody said to me the other day, they were like, ‘Is Black Widow ready for the Guardians of the Galaxy?’ The last time aliens descended on New York I think my character was like, ‘Alright, I’ve seen it all. I’m good.’ So I don’t even think like a talking tree will faze her at this point.”
It makes sense that Black Widow would meet the Guardians with her usual calm demeanor. After all, her last almost-boyfriend was a giant green rage monster. While everyone else is still startled by these things, Romanoff has gone through enough at this point that the Guardians probably would seem like just another batch of weirdos.
“As long as it feels true to me, then this conversation with another character is fine, even if it’s a tree.”
Seeing Groot talk to the various members of the Avengers will be a sight to behold, and we’re all curious to see how each of the Avengers will react to Rocket. Still, talking alien trees and raccoons are a far cry from the MCU’s more grounded beginnings, a fact that Johansson pointed out in her interview:
“But certainly, reading the script, the universe has expanded to a point where it just… it’s like incomprehensible at this point I’m just like, ‘Okay, this is all happening,’”
Are you excited as she is? How do you think the Guardians and Avengers will interact with each other? Let us know in the comments below!
Source: International Business Times |
A hidden Markov model for transcriptional regulation in single cells.
We discuss several issues pertaining to the use of stochastic biochemical systems for modeling transcriptional regulation in single cells. By appropriately choosing the system state, we can model transcriptional regulation by a hidden Markov model (HMM). This opens the possibility of using well-known techniques for the statistical analysis and stochastic control of HMMs to mathematically and computationally study transcriptional regulation in single cells. Unfortunately, in all but a few simple cases, analytical characterization of the statistical behavior of the proposed HMM is not possible. Moreover, analysis by Monte Carlo simulation is computationally cumbersome. We discuss several techniques for approximating the HMM by one that is more tractable. We employ simulations, based on a biologically relevant transcriptional regulatory system, to show the relative merits and limitations of various approximation techniques and provide general guidelines for their use. |
(provide 'common2.scm)
#!!
(c-define-expansion (*match-old* args . matchers)
(define matcher-func (gensym "matcher-func"))
(eval
`(let ()
(define-match ,matcher-func
,@matchers)
(apply ,matcher-func ,args))))
!!#
(c-define-expansion (*match* args . matchers)
`(begin
(eval (create-matcher-func 'matcher-func-temp-name ',matchers))
(<declare-variable> matcher-func-temp-name)
(apply matcher-func-temp-name ,args)))
#!!
(pretty-print (macroexpand (define-match is-define-lazy
(define-lazy _ _ ) :> #t
__________________ :> #f)))
(test (match (list 'a 'b)
a b :> 5
_ _ :> #f)
5)
(match (list 'a 'b)
a b :> 5
_ :> 9)
(let-ref (rootlet) 'aiai2)
(defined? 'aiai (rootlet))
(procedure-source setaiai!)
(define (setaiai! val)
(varlet (rootlet) 'aiai val))
!!#
(define (time)
(*s7* 'cpu-time))
(define (safe-scale x x1 x2 y1 y2)
(let ((div (- x2 x1)))
(if (= div 0)
(begin
(<declare-variable> safe-add-message-window-txt)
(safe-add-message-window-txt (string-append "Error. Almost divided by zero in safe-scale: (= (- x2 x1) 0) " (number->string x2) " " (number->string x1)))
0)
(+ y1 (/ (* (- x x1)
(- y2 y1))
(- x2 x1))))))
(assert (= 0 (max 0 -1/2)))
(define (random-shuffle seq)
(define v (to-vector seq))
(define size (length v))
(if (< size 2)
seq
(begin
(for-each (lambda (to-pos)
(define from-pos (integer-myrand to-pos (1- size)))
(define to-val (v to-pos))
(define from-val (v from-pos))
;;(c-display "swapping " to-pos from-pos)
(set! (v to-pos) from-val)
(set! (v from-pos) to-val))
(integer-range 0 (- size 2)))
(if (vector? seq)
v
(to-list v)))))
#!!
(random-shuffle '(6 2 3 1))
(random-shuffle '())
(random-shuffle '(4))
(random-shuffle '(5 2))
!!#
;; uses "chance" to determine the chance of swapping two sequential elements
(define (light-shuffle seq chance)
(let loop ((seq (to-list seq)))
(if (or (null? seq)
(null? (cdr seq)))
seq
(let ((element1 (car seq))
(element2 (cadr seq)))
(if (>= chance (myrand 0 1))
(if #f
(append (list element2 element1)
(loop (cddr seq)))
(cons element2
(loop (cons element1
(cddr seq)))))
(cons element1
(loop (cdr seq))))))))
#!!
(light-shuffle '(1 2 3 4) 0.0)
!!#
;; (round 2.5) -> 2
;; (roundup 2.5) -> 3
(define (roundup A)
(floor (+ A 0.5)))
(define (unit-ceiling value unit)
(* unit (ceiling (/ value unit))))
(***assert*** (unit-ceiling 5 5)
5)
(***assert*** (unit-ceiling 10 10)
10)
(***assert*** (unit-ceiling 5.2 1)
6)
(***assert*** (unit-ceiling 5.2 2)
6)
(***assert*** (unit-ceiling 5.2 3)
6)
(***assert*** (unit-ceiling 5.2 4)
8)
(***assert*** (unit-ceiling 5.2 5)
10)
(***assert*** (unit-ceiling 5.2 6)
6)
(define (unit-floor value unit)
(* unit (floor (/ value unit))))
(define (unit-round value unit)
(* unit (round (/ value unit))))
(define (two-decimals val)
(/ (roundup (* val 100))
100.0))
(define (one-decimal-string number)
(format #f "~,1F" (* 1.0 number)))
(define (two-decimal-string number)
(format #f "~,2F" (* 1.0 number)))
(define (three-decimal-string number)
(format #f "~,3F" (* 1.0 number)))
(define (one-decimal-percentage-string number)
(format #f "~,1F" (* 100.0 number)))
(define (get-displayable-seconds s)
(if (< s 60)
(<-> (if (< s 10)
" "
"")
(two-decimal-string s)
"s")
(let* ((minutes (floor (/ s 60)))
(seconds (floor (- s (* minutes 60)))))
(<-> (if (< minutes 10)
(<-> " " minutes)
minutes)
":"
(if (< seconds 10)
(<-> "0" seconds)
seconds)
"m"))))
(define (to-integer A)
(inexact->exact (floor A)))
(define (to-boolean A)
(if A #t #f))
(define (to-list A)
(if (vector? A)
(vector->list A)
A))
(define (to-vector A)
(if (list? A)
(list->vector A)
A))
(define (min-notfalse . Args)
(match (list Args)
() :> #f
(N) :> N
(#f . Rest) :> (apply min-notfalse Rest)
(N . Rest) :> (let ((that (apply min-notfalse Rest)))
(if that
(min N that)
N))))
#||
(test (min-notfalse)
#f)
(test (min-notfalse #f)
#f)
(test (min-notfalse #f 5)
5)
(test (min-notfalse 5 #f)
5)
(test (min-notfalse 8 #f 5)
5)
||#
(define (max-notfalse . Args)
(match (list Args)
() :> #f
(N) :> N
(#f . Rest) :> (apply max-notfalse Rest)
(N . Rest) :> (let ((that (apply max-notfalse Rest)))
(if that
(max N that)
N))))
#||
(test (max-notfalse)
#f)
(test (max-notfalse #f)
#f)
(test (max-notfalse #f 5)
5)
(test (max-notfalse 5 #f)
5)
(test (max-notfalse 8 #f 5)
8)
||#
(define (get-procedure-name procedure)
(let ((maybe (format #f "~S" procedure)))
(if (string-starts-with? maybe "#")
""
maybe)))
#!!
;;(c-display "doc:" (documentation procedure))
(let ((doclist (string-split (documentation procedure) #\space)))
;;(c-display "DOCLIST: -" doclist "-")
(if (null? doclist)
""
(if (string=? "" (car doclist))
""
(string-drop (car doclist) 1)))))
!!#
#!!
(get-procedure-name (lambda () #t))
!!#
;; force and delay are missing from s7. Simple implementation below.
(c-define-expansion (*delay* . body)
`(vector #f
#f
(lambda ()
,@body)))
(define (force something)
(if (not (vector-ref something 0))
(begin
(vector-set! something 1 ((vector-ref something 2)))
(vector-set! something 0 #t)))
(vector-ref something 1))
#||
(define a (delay
(c-display "hello")
50))
(c-display a)
(force a)
||#
;; copy-hash
(define (copy-hash hash . rest)
(define ret (copy hash))
(let loop ((rest rest))
(if (null? rest)
ret
(let ((key (car rest))
(value (cadr rest)))
(hash-table-set! ret key value)
(loop (cddr rest))))))
(***assert*** (copy-hash (hash-table :a 9 :b 10 :c 'a)
:a 8
:b 11)
(hash-table :a 8
:b 11
:c 'a))
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;; define-struct ;;;;;;;;;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define-match keyvalues-to-define-args
() :> '()
(Key) :> (cons (list (keyword->symbol Key) ''must-be-defined)
'())
(Key1 Key2 . Rest) :> (cons (list (keyword->symbol Key1) ''must-be-defined)
(keyvalues-to-define-args (cons Key2 Rest)))
:where (keyword? Key2)
(Key Value . Rest) :> (cons (list (keyword->symbol Key) Value)
(keyvalues-to-define-args Rest)))
#||
(test (keyvalues-to-define-args '(:a 90 :b 50 :c :d 80))
'((a 90) (b 50) (c 'must-be-defined) (d 80)))
(test (keyvalues-to-define-args '(:a 90 :b 50 :c))
'((a 90) (b 50) (c 'must-be-defined)))
||#
(define (copy-struct-helper original struct-name keys arguments)
(if (keyword? original)
(error 'not-a-struct-but-a-keyword (<-> "Copy " struct-name " struct: First argument is not a struct, but a keyword")))
;; check that new data is valid
(let loop ((arguments arguments))
(if (not (null? arguments))
(let ((key (car arguments))
(value (cadr arguments)))
(if (not (memq (keyword->symbol key) keys))
(error 'key-not-found-in-struct1 (<-displayable-> "key '" key (<-> "' not found in struct '" struct-name "'") ". keys: " (map symbol->keyword keys))))
(loop (cddr arguments)))))
(define new-table (copy original)) ;; No worries. 'new-table' will contain the "(cons eq? ,struct-mapper)" argument similar to 'original'.
;; add new data
(let loop ((arguments arguments))
(if (not (null? arguments))
(let ((key (car arguments))
(value (cadr arguments)))
(hash-table-set! new-table key value)
(loop (cddr arguments)))))
new-table)
(c-define-expansion (*define-struct* name . args)
(define define-args (keyvalues-to-define-args args))
(define keys (map car define-args))
(define keys-length (length keys))
(define must-be-defined (keep (lambda (arg)
(equal? ''must-be-defined (cadr arg)))
define-args))
(define table (gensym "table"))
(define key (gensym "key"))
(define keysym (gensym "keysym"))
(define ret (gensym "ret"))
(define keysvar (gensym "keys"))
(define keysvar2 (gensym "keys2"))
(define original (gensym "original"))
(define arguments (gensym "arguments"))
(define loop (gensym "loop"))
(define n (gensym "n"))
(define struct-mapper (<_> name '-struct-mapper))
`(begin
(define ,struct-mapper
(let ((keytablemapper (make-hash-table ,keys-length eq?)))
(for-each (lambda (key n)
(hash-table-set! keytablemapper (symbol->keyword key) n))
(quote ,keys)
(iota ,keys-length))
(lambda (key)
(or (keytablemapper key)
(error 'key-not-found-in-struct2 (<-displayable-> "key " (keyword->symbol key) ,(<-> " not found in struct '" name "'") ". keys: " (quote ,keys)))))))
(define (,(<_> '<copy- name '>) ,original . ,arguments)
(copy-struct-helper ,original
(quote ,name)
(quote ,keys)
,arguments))
(define (,(<_> 'copy- name) ,original . ,arguments)
(copy-struct-helper ,original
(quote ,name)
(quote ,keys)
,arguments))
(define (,(<_> 'make- name '-nokeywords) ,@(map car (keyvalues-to-define-args args)))
(let* ((,table (make-hash-table ,keys-length (cons eq? ,struct-mapper)))
(,keysvar (quote ,keys)))
,@(map (lambda (key)
`(hash-table-set! ,table ,(symbol->keyword key) ,key))
keys)
,table))
(define* (,(<_> 'make- name) ,@(keyvalues-to-define-args args))
,@(map (lambda (must-be-defined)
`(if (eq? ,(car must-be-defined) 'must-be-defined)
(error 'missing-key-when-making-struct ,(<-> "key '" (car must-be-defined) "' not defined when making struct '" name "'"))))
must-be-defined)
(let* ((,table (make-hash-table ,keys-length (cons eq? ,struct-mapper)))
(,keysvar (quote ,keys)))
,@(map (lambda (key)
`(hash-table-set! ,table ,(symbol->keyword key) ,key))
keys)
,table))))
#||
(define-struct test
:b 59
:c)
(make-test-nokeywords 3 4)
(make-test 3 4)
(define t (make-test :c 2))
(t :b)
(t :c)
(t :dir)
(define t2 (copy-test t :b 80))
(t2 :b)
(t2 :c)
(t2 :dir)
;; error, unknown key:
(copy-test t :unknown-key 2))
(define t2 (copy-test t :b 2))
(t2 :b)
(pretty-print (macroexpand (define-struct teststruct
:a 'asdf
:b
:c #f)))
(pretty-print (macroexpand
(define-struct test
:b 59
:c)))
(hash-table* :a 9 :b 8)
(make-test :b 33)
(define t (make-test :c 2))
(t :b)
(t :c)
(t :dir)
(t :bc)
(t :b)
(hash-table-set! t :b 8)
(define t2 (t :copy :b 2))
(define tab (make-hash-table 32 eq?))
(hash-table-set! tab :hello 2)
(hash-table-set! tab :hello 3)
(tab :hello)
||#
;; doesn't "(morally-equal? hash-table1 hash-tabl2)" work? (not always, morally-equal? doesn't call my-equal?).
(define (structs-equal? a b)
(morally-equal? a b))
#||
(define alist-a a)
(define alist-b b)
(define keys-a (map car alist-a))
(and (= (length keys-a)
(length alist-b))
(let loop ((keys-a keys-a))
(if (null? keys-a)
#t
(and (my-equal? (a (car keys-a))
(b (car keys-a)))
(loop (cdr keys-a)))))))
||#
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;; delafina ;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define-match delafina-args-to-define*-args
() :> '()
(Var . Rest) :> (error 'delafina-error (<-> "All parameters for delafina must be keywords. '" Var "' is not a keyword"))
:where (not (keyword? Var))
(Key) :> (list (keyword->symbol Key))
(Key1 Key2 . Rest) :> (cons (keyword->symbol Key1)
(delafina-args-to-define*-args (cons Key2 Rest)))
:where (keyword? Key2)
(Key Value . Rest) :> (cons (list (keyword->symbol Key) Value)
(delafina-args-to-define*-args Rest)))
(c-define-expansion (*delafina* def . body)
`(define* (,(car def) ,@(delafina-args-to-define*-args (cdr def)))
,@body))
#||
(pretty-print (macroexpand (delafina (testfunc :b 30 :c 90)
(+ 2 3)
(+ 5 6))))
(pretty-print (macroexpand (delafina (testfunc :a :b :c 30 :d 90 :e f g)
(+ 2 3)
(+ 5 6))))
(test (macroexpand (delafina (testfunc a b :c 30 :d 90) a b))
'(define* (testfunc a b (c 30) (d 90)) a b))
(define* (aiai (a 5) b (c 20))
(list a b c))
(aiai)
(define* (aiai2 a b c)
(list a b c))
(aiai2 2 3 4 5 6)
||#
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;; Try - Catch - Finally ;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;
;;
#||
"eat-errors" is NOT the same as dynamic-wind. It doesn't rethrow. I.e. the code following a call to "eat-errors" should always run [1].
Also note that the :finally thunk doesn't have an important purpose. It's just syntactic sugar. This:
(eat-errors :try (lambda () 5)
:finally newline)
...is the same as this:
(let ((ret (eat-errors :try (lambda () 5))))
(newline)
ret)
[1] At least in the normal situations, not too sure about what happens if there is creative use of call/cc.
||#
(define-constant *try-finally-rethrown* (gensym "try-finally-rethrown"))
(define (catch-args-are-from-try-finally args)
(and (not (null? args))
(symbol? (car args))
(eq? *try-finally-rethrown* (car args))))
#!!
(+ notanumber1 notanumber2)
(error *try-finally-rethrown*)
(begin
(error *try-finally-rethrown*)
(awefoaijweogijareg))
!!#
;;
;;
;;
;; A helper function:
(define (catch-all-errors-and-display-backtrace-automatically thunk)
(catch #t
thunk
(lambda args
(display "(catch-all-errors-and-display-backtrace-automatically thunk) failed. args:")(newline)
(display args)(newline)
(when (not (catch-args-are-from-try-finally args))
(catch #t
safe-display-ow!
(lambda args
(error 'safe-display-ow!-failed))))
*eat-errors-failed-return-value*)))
(define (catch-all-errors-failed? ret)
(eq? ret *eat-errors-failed-return-value*))
;; Then the function we want to use everywhere:
(define-constant *eat-errors-failure-thunk-failed* 'eat-errors-failure-thunk-failed)
(define-constant *eat-errors-false-unless-failure-is-overridden* 'false-unless-failure-is-overridden)
(delafina (eat-errors :try
:rethrow #f
;; If overridden, :failure will always return this value. If not overridden, the default :failure implementation will return #f.
:failure-return-value *eat-errors-false-unless-failure-is-overridden*
:failure (lambda ()
(if (eq? failure-return-value *eat-errors-false-unless-failure-is-overridden*)
#f
failure-return-value))
:finally (lambda ()
#f))
(define (return ret maybe-rethrow)
(finally)
(if (and rethrow maybe-rethrow)
(throw *try-finally-rethrown*)
ret))
(define try-ret (catch-all-errors-and-display-backtrace-automatically try))
(if (catch-all-errors-failed? try-ret)
(begin
(define failed-ret (catch-all-errors-and-display-backtrace-automatically failure))
(cond ((catch-all-errors-failed? failed-ret)
(return *eat-errors-failure-thunk-failed* #t))
((eq? failure-return-value *eat-errors-false-unless-failure-is-overridden*)
(return failed-ret #t))
(else
(return failure-return-value #t))))
(return try-ret #f)))
(delafina (try-finally :try
:failure #f
:failure-return-value *eat-errors-false-unless-failure-is-overridden*
:finally (lambda ()
#f))
(if failure
(eat-errors :try try
:rethrow #t
:failure failure
:finally finally)
(eat-errors :try try
:rethrow #t
:finally finally)))
(c-display "\n\n\n\n=======================================================================================================")
(c-display " START testing try-catch-failure. Lots of backtrace will be printed, but nothing is wrong, hopefully.")
(c-display "=======================================================================================================\n\n\n\n")
;; Test try-finally
(let* ((somethingspecial (gensym "somethingspecial")))
(***assert*** (let ((should-be-somethingspecial somethingspecial))
(eat-errors :try (lambda ()
(try-finally :try (lambda ()
(<declare-variable> weofij)
(<declare-variable> oiwgrjoewrgi)
(+ weofij oiwgrjoewrgi)))
(ra:play-block-from-start)
(set! should-be-somethingspecial 'not-so-special)
(<declare-variable> aoregijoaija)
(<declare-variable> aeorgijaoirgje)
(+ aoregijoaija aeorgijaoirgje))
:finally (lambda ()
50))
(assert (not (ra:is-playing-block)))
should-be-somethingspecial)
somethingspecial))
;; Test all fine.
(***assert*** (eat-errors :try (lambda ()
(c-display "returning 4")
(+ 1 3))
:rethrow #f)
4)
;; Test all fine with finalizer
(let ((is-finalized #f))
(***assert*** (eat-errors :try (lambda ()
(c-display "returning 5")
(+ 2 3))
:finally (lambda ()
(c-display "finally")
(set! is-finalized #t)))
5)
(***assert*** is-finalized #t))
;; Test all fine and catch not called.
(let ((is-finalized #f)
(is-catched #f))
(***assert*** (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ 2 3))
:failure (lambda ()
(c-display "catching")
(***assert*** is-finalized #f)
(set! is-catched #t))
:finally (lambda ()
(c-display "finally")
(***assert*** is-catched #f)
(set! is-finalized #t)))
5)
(***assert*** is-finalized #t)
(***assert*** is-catched #f))
(<declare-variable> *undefined-var*)
(<declare-variable> *undefined-var2*)
;; Test failure in 'try'. Returns #f by default.
(let ((is-finalized #f))
(define result (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:failure-return-value 281
:finally (lambda ()
(c-display "finally")
(set! is-finalized #t))))
(***assert*** result 281)
(***assert*** is-finalized #t))
;; Test failure in 'try'. Custom failure function.
(let ((is-finalized #f))
(define result (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:finally (lambda ()
(c-display "finally")
(set! is-finalized #t))))
(***assert*** result #f)
(***assert*** is-finalized #t))
;; Test failure in 'try'. Custom failure func.
(let ((is-finalized #f)
(is-catched #f))
(define result (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:failure (lambda ()
(c-display "catching")
(***assert*** is-finalized #f)
(set! is-catched #t)
'failed)
:finally (lambda ()
(c-display "finally")
(***assert*** is-catched #t)
(set! is-finalized #t))))
(***assert*** result 'failed)
(***assert*** is-finalized #t)
(***assert*** is-catched #t))
;; Test failure in 'try'. Custom failure function and custom failure return value.
(let ((is-finalized #f)
(is-catched #f))
(define result (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:failure-return-value 281
:failure (lambda ()
(c-display "catching")
(***assert*** is-finalized #f)
(set! is-catched #t)
'failed)
:finally (lambda ()
(c-display "finally")
(***assert*** is-catched #t)
(set! is-finalized #t))))
(***assert*** result 281)
(***assert*** is-catched #t)
(***assert*** is-finalized #t))
;; Test failure in 'failure'. (a lot of backtrace is supposed to be printed now, but the important thing is that the last three asserts are correct.)
(let ((is-finalized #f)
(is-catched #f))
(define result (eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:failure (lambda ()
(c-display "catching")
(***assert*** is-finalized #f)
(set! is-catched #t)
(+ *undefined-var2* 4)
'failed)
:finally (lambda ()
(c-display "finally")
(***assert*** is-catched #t)
(set! is-finalized #t))))
(***assert*** result *eat-errors-failure-thunk-failed*)
(***assert*** is-finalized #t)
(***assert*** is-catched #t))
;; Test failure in 'finally'. (we test that a failure in 'finally' is not caught)
(let ((is-finalized #f)
(is-catched #f)
(finally-failed #f))
(define result (catch #t
(lambda ()
(eat-errors :try (lambda ()
(c-display "returning 5")
(***assert*** is-finalized #f)
(+ *undefined-var* 3))
:failure (lambda ()
(c-display "catching")
(***assert*** is-finalized #f)
(set! is-catched #t)
(+ *undefined-var2* 4)
'failed)
:finally (lambda ()
(c-display "finally")
(***assert*** is-catched #t)
(set! is-finalized #t)
(<declare-variable> c)
(+ c 5))))
(lambda args
(set! finally-failed #t)
'finally-failed2)))
(***assert*** result 'finally-failed2)
(***assert*** finally-failed #t)
(***assert*** is-finalized #t)
(***assert*** is-catched #t))
(c-display "\n\n\n\n=======================================================================================================")
(c-display " FINISHED testing try-catch-failure. Lots of backtrace was printed, but nothing is wrong, hopefully.")
(c-display "=======================================================================================================\n\n\n\n")
(c-define-expansion (*with-history-disabled* . code)
`(begin
(ra:disable-scheme-history)
(try-finally :try (lambda ()
,@code)
:finally ra:enable-scheme-history)))
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;; Box handling ;;;;;;;;;;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define-struct box :x :y :x1 :y1 :x2 :y2 :width :height)
(define (make-box2 $x1 $y1 $x2 $y2)
(make-box :x (average $x1 $x2)
:y (average $y1 $y2)
:x1 $x1
:y1 $y1
:x2 $x2
:y2 $y2
:width (- $x2 $x1)
:height (- $y2 $y1)))
(c-define-macro (*ra:get-box* prefix . rest)
`(make-box2 ( ,(<_> 'ra:get- prefix '-x1) ,@rest)
( ,(<_> 'ra:get- prefix '-y1) ,@rest)
( ,(<_> 'ra:get- prefix '-x2) ,@rest)
( ,(<_> 'ra:get- prefix '-y2) ,@rest)))
(c-define-expansion (*ra:get-box2* prefix . rest)
`(make-box2 ( ,(<_> 'ra:get- prefix '-x1) ,@rest)
( ,(<_> 'ra:get- prefix '-y1) ,@rest)
( ,(<_> 'ra:get- prefix '-x2) ,@rest)
( ,(<_> 'ra:get- prefix '-y2) ,@rest)))
(define (box-to-string box)
(if (not box)
"<box is #f>"
(<-> "(box"
" :x1 " (box :x1)
" :y1 " (box :y1)
" :x2 " (box :x2)
" :y2 " (box :y2)
" :width " (box :width)
" :height " (box :height)
")")))
#||
(pretty-print (macroexpand (define-struct box :x1 :y1 :x2 :y2)))
(list
((ra:get-box reltempo-slider) :x1)
((ra:get-box reltempo-slider) :y1)
((ra:get-box reltempo-slider) :x2)
((ra:get-box reltempo-slider) :y2)
((ra:get-box reltempo-slider) :width)
((ra:get-box reltempo-slider) :height))
||#
(define (inside-box? box x y)
;;(c-display "Whtas the box:" box)
(and (>= x (box :x1))
(< x (box :x2))
(>= y (box :y1))
(< y (box :y2))))
#||
||#
(define (inside-box-forgiving? Box X Y) ;; Inside a box, inluding half the width of a node.
(define width/2 (1+ (ra:get-half-of-node-width)))
(and (>= X (- (Box :x1) width/2))
(< X (+ (Box :x2) width/2))
(>= Y (- (Box :y1) width/2))
(< Y (+ (Box :y2) width/2))))
;; Replaces all occurences of A with B in List
(define-match deep-list-replace
A B A :> B
_ _ ( ) :> '()
A B (R . Rest) :> (cons (deep-list-replace A B R)
(deep-list-replace A B Rest))
A B C :> C)
#||
(test (deep-list-replace 1 2 1)
2)
(test (deep-list-replace '() 2 '())
2)
(test (deep-list-replace 1 2 3)
3)
(test (deep-list-replace 1 2 '(1 1))
'(2 2))
(test (deep-list-replace 1 2 '(1 1 . 1))
'(2 2 . 2))
(test (deep-list-replace 1 2 '(1 (1 . 1) 2 (2 . 1) (3 1)))
'(2 (2 . 2) 2 (2 . 2) (3 2)))
||#
(define-match deep-list-replace-several
() List :> List
((A B) . ABs) List :> (deep-list-replace-several ABs
(deep-list-replace A B List)))
#||
(test (deep-list-replace-several '((1 2)(3 4)) '(1 3))
'(2 4))
(test (deep-list-replace-several '((a (force a))) '(+ a a a))
'(+ (force a) (force a) (force a)))
||#
#||
for .emacs:
(font-lock-add-keywords
'scheme-mode
'(("(\\(define-lazy\\)\\>\\s-*(?\\(\\sw+\\)?"
(1 font-lock-keyword-face)
(2 font-lock-type-face)
(3 (cond ((match-beginning 1) font-lock-function-name-face)
((match-beginning 2) font-lock-variable-name-face)
((match-beginning 3) font-lock-function-name-face)
(t font-lock-type-face))
nil t))))
(font-lock-add-keywords
'scheme-mode
'(("(\\(lazy\\)\\>\\s-*(?\\(\\sw+\\)?"
(1 font-lock-keyword-face)
(2 (cond ((match-beginning 1) font-lock-function-name-face)
((match-beginning 2) font-lock-variable-name-face)
(t font-lock-type-face))
nil t))))
||#
(define-match is-define-lazy
(define-lazy _ _ ) :> #t
__________________ :> #f)
(define-match get-lazy-replacement
(define-lazy Name _____) :> `(,Name (force ,Name))
________________________ :> (error 'something-went-wrong-in-get-lazy-replacement-in-lazy))
(define-match transform-lazy-code
Replacements (define-lazy Name Value) :> `(define ,Name (delay ,(deep-list-replace-several Replacements Value)))
____________ _________________________ :> #f)
(c-define-expansion (*lazy* . body)
;;(c-display "EXPSNDFING lazy macro")
(define lazy-vals (keep is-define-lazy body))
(define lazy-replacements (map get-lazy-replacement lazy-vals))
(define lazy-vals-code (map (lambda (lazy-val)
(transform-lazy-code lazy-replacements lazy-val))
lazy-vals))
(define rest-body (remove is-define-lazy body))
(define rest-body-code (deep-list-replace-several lazy-replacements rest-body))
`(begin
,@lazy-vals-code
,@rest-body-code))
#||
(test (lazy
(define-lazy a 50)
(define-lazy b 60)
(+ a b))
110)
(define-expansion (lazy2 . body)
(define-match hepp
_ :> "hepp")
`(begin
(c-display ,(hepp #t))
,@body))
(define (hepp)
(lazy2
;;(define-lazy a 50)
60))
(hepp)
(lazy2 5)
(macroexpand (lazy 60))
(test (let ((val 0))
(lazy
(define-lazy a (begin
(set! val (+ val 1))
val))
(+ a a a)))
3)
(test (lazy
(define-lazy a 5)
(define-lazy b a)
b)
5)
(pretty-print (macroexpand (lazy
(define-lazy a 5)
(define-lazy b a)
b)))
(macroexpand (lazy
(define-lazy a (begin
(set! val (+ val 1))
val))
(+ a a a)))
(macroexpand (lazy
(define-lazy a 50)
(define-lazy b 60)
(+ a b)))
||#
(define (group-by get-key key-compare elements)
(define keys '())
(define hash (make-hash-table 39 key-compare))
(for-each (lambda (element)
(let* ((key (get-key element))
(old-value (hash-table-ref hash key)))
(if (not old-value)
(push-back! keys key))
(hash-table-set! hash
key
(cons element
(or old-value '())))))
elements)
(map (lambda (key)
(reverse! (hash-table-ref hash key)))
keys))
(***assert*** (group-by (lambda (x)
x)
=
'(1 5 2 3 5 1))
'((1 1)
(5 5)
(2)
(3)))
(define true-for-all? every?)
(***assert*** (true-for-all? even? '())
#t)
(***assert*** (true-for-all? even? '(2 4 6))
#t)
(***assert*** (true-for-all? even? '(2 4 3))
#f)
(define (true-for-at-least-one? pred elements)
(if (null? elements)
#f
(or (pred (car elements))
(true-for-at-least-one? pred (cdr elements)))))
(***assert*** (true-for-at-least-one? even? '())
#f)
(***assert*** (true-for-at-least-one? even? '(2 4 6))
#t)
(***assert*** (true-for-at-least-one? even? '(2 4 3))
#t)
(***assert*** (true-for-at-least-one? even? '(1 9 3))
#f)
;; Precompute all iota results up to, and including, 1024.
(let* ((org-iota iota)
(iota-results (list->vector (map (lambda (n)
(org-iota n))
(org-iota 1026)))))
;;(c-display "res" iota-results)
(set! iota
(lambda (n)
(if (< n 1025)
(iota-results n)
(org-iota n)))))
(define (vector-copy vector*)
(copy vector*))
;; cl-car and cl-cdr moved to mylint.scm
;;
(define (cl-cddr a)
(cl-cdr (cl-cdr a)))
(define (cl-cadr a)
(cl-car (cl-cdr a)))
(define (cl-caddr a)
(cl-car (cl-cdr (cl-cdr a))))
(define (cl-cadddr a)
(cl-car (cl-cdr (cl-cdr (cl-cdr a)))))
(***assert*** (butlast '(2)) '())
(***assert*** (butlast '(2 3)) '(2))
(define (map-butlast elements func)
(if (null? elements)
elements
(append (map func
(butlast elements))
(list (last elements)))))
;;(define (second-last elements)
;; (cadr (reverse elements)))
(define (second-last alist)
(if (null? (cddr alist))
(car alist)
(second-last (cdr alist))))
(***assert*** (second-last '(1 2))
1)
(***assert*** (second-last '(1 2 3))
2)
;; like list-set! except that it doesn't modify the list
(define (list-replace-element das-list pos new-value)
(if (= 0 pos)
(cons new-value
(cdr das-list))
(cons (car das-list)
(list-replace-element (cdr das-list)
(1- pos)
new-value))))
(define (list-remove das-list pos)
(if (= 0 pos)
(cdr das-list)
(cons (car das-list)
(list-remove (cdr das-list)
(1- pos)))))
(***assert*** (list-remove '(0 1 2) 0) '(1 2))
(***assert*** (list-remove '(0 1 2) 1) '(0 2))
(***assert*** (list-remove '(0 1 2) 2) '(0 1))
;; Comparer must return #t if its two arguments are equal and false if not.
(define (remove-duplicates-in-sorted-list comparer das-list)
(if (null? das-list)
'()
(let ((a (car das-list)))
(if (null? (cdr das-list))
das-list
(let ((b (cadr das-list)))
(if (comparer a b)
(remove-duplicates-in-sorted-list comparer (cdr das-list))
(cons a
(remove-duplicates-in-sorted-list comparer (cdr das-list)))))))))
(define (remove-duplicates less-than equal das-list)
(remove-duplicates-in-sorted-list equal
(sort das-list less-than)))
#!!
(remove-duplicates < = '(8 2 2 5 7))
(remove-duplicates-in-sorted-list = '(1 1 8 9 10 10))
(< 1 2)
(procedure-source remove-duplicates3)
(gakk)
(string<? "ab" "bb")
!!#
(define (integer-range start-inclusive end-inclusive)
(map (lambda (i)
(+ i start-inclusive))
(iota (1+ (- end-inclusive start-inclusive)))))
(***assert*** (integer-range 0 5)
'(0 1 2 3 4 5))
(***assert*** (integer-range 5 5)
'(5))
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;; define-class ;;;;;;;;;;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define (define-class-helper class-name hash-table-name methods)
(define this-method-names (map (lambda (method)
;;(c-display "METHOD" method)
(<_> 'this-> (keyword->symbol (car method))))
methods))
(define this-methods (map (lambda (this-method-name method)
(define args (cadr method))
(define body (cddr method))
(if (pair? args)
`(define (,this-method-name ,@args)
,@body)
`(define (,this-method-name . ,args)
,@body)))
this-method-names
methods))
`(,@this-methods
,@(map (lambda (method-name method)
`(hash-table-set! ,hash-table-name ,(car method) ,method-name))
this-method-names
methods)
this))
(***assert*** (define-class-helper 'list-and-set 'methods_of_list-and-set
'((:contains (key)
(hash key))
(:list ()
alist)
(:set ()
hash)))
'((define (this->contains key)
(hash key))
(define (this->list)
alist)
(define (this->set)
hash)
(hash-table-set! methods_of_list-and-set :contains this->contains)
(hash-table-set! methods_of_list-and-set :list this->list)
(hash-table-set! methods_of_list-and-set :set this->set)
this))
(c-define-expansion (*<define-class-with-custom-definer>* definer signature . rest)
(define class-name (string->symbol (list->string (butlast (cdr (string->list (symbol->string (car signature))))))))
(define new-class-name (<_> 'new_instance_of_ class-name))
(define args (cdr signature))
(define body '())
(define methods '((:add-method! (name func) (add-method! name func))))
(define hash-table-name (<_> 'methods_of_ class-name))
(let loop ((rest rest)
(has-methods #f))
(when (not (null? rest))
(cond ((keyword? (car rest))
(push-back! methods (list (car rest) (cadr rest) (caddr rest)))
(loop (cdddr rest) #t))
(else
(assert (not has-methods))
(push-back! body (car rest))
(loop (cdr rest) #f)))))
(append (cons definer (list (cons new-class-name args)))
`((define ,hash-table-name (make-hash-table ,(+ 2 (length methods)) eq?))
(define (this methodname . rest)
;;(c-display " CALLING THIS" methodname ,hash-table-name)
(let ((func (,hash-table-name methodname)))
;;(c-display " CALLING THIS2" methodname func)
(if func
(apply func rest)
(error (<-> "Method \"" methodname ,(<-> "\" not found in class " class-name ". methods: ") (map car ,hash-table-name))))))
(define (add-method! name func)
(hash-table-set! ,hash-table-name name func)))
body
(define-class-helper class-name hash-table-name methods)))
(c-define-expansion (*define-class* signature . rest)
(append '(<define-class-with-custom-definer>) '(delafina) (list signature)
rest))
(c-define-expansion (*<new>* class-name . args)
`(,(<_> 'new_instance_of_ (keyword->symbol class-name)) ,@args))
#!!
(pretty-print
(define-class-helper 'list-and-set 'hello
'((:contains x
(hash key)))))
(pretty-print
(macroexpand
(define-class (<test-class>)
(define (dosomething a b)
;;(c-display a b)
50
)
:dosomething x
(apply dosomething x))))
(pretty-print
(macroexpand
(<define-class-with-custom-definer>
delafina
(<test-class>)
(define (dosomething a b)
50)
:dosomething x
(apply dosomething x))))
(define-class (<test-class>)
(define (dosomething a b)
(+ a b))
:dosomething x
(apply dosomething x))
(define testinstance (<new> :test-class))
(testinstance :dosomething 5 9)
(testinstance :add-method! :ai (lambda ()
(c-display "ai called")))
(testinstance :ai)
(begin
(newline)
(pretty-print
(macroexpand
(define-class (<test-class>)
)))
(newline))
(begin
(newline)
(pretty-print
(macroexpand (<define-class-with-custom-definer> delafina (<test-class>)))
)
(newline))
(define-class (<test-class>)
(define (dosomething a b)
(c-display a b this)
50
)
:dosomething x
(apply dosomething x))
(define testinstance (<new> :test-class))
(testinstance :dosomething 5 9)
!!#
#||
(pretty-print
(macroexpand
(define-class (list-and-set :alist
:eq-func eq?)
(define hash (make-hash-table (max 1 (length alist)) eq-func))
(for-each (lambda (element)
(set! (hash element) #t))
alist)
;;
((:contains (key)
(hash key))
(:list ()
alist)
(:set ()
hash))
)
)
)
||#
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;;;;;;;;;;;;; container ;;;;;;;;;;;;;;;;
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define-class (<container> :elements ;; <-- elements must be either a list, a vector, or a hash table (only the keys are used in the hash table, the values must not be #f (impossible in s7)).
:eq-func #f) ;; <-- #if #f, automatically determined, but should be set anyway. If elements is a hash table, eq-func is not used.
(define vector* #f)
(define list* #f)
(define-optional-hash-table hash)
(define num-elements #f)
(define (clear! new-elements new-vector new-list new-hash new-num-elements)
(set! elements new-elements)
(set! vector* (if new-vector
vector*
(if (vector? new-elements)
new-elements
#f)))
(set! list* (if new-list
new-list
(if (pair? new-elements)
new-elements
#f)))
(set! hash (if new-hash
new-hash
(if (hash-table? new-elements)
new-elements
#f)))
(set! num-elements (if new-num-elements
new-num-elements
(cond (vector*
(vector-length new-elements))
(hash
(hash-table-entries hash))
(else
#f)))))
(clear! elements #f #f #f #f)
(define (get-eq-func)
(when (not eq-func)
(set! eq-func (if (= 0 (get-size))
morally-equal?
(let ((el0 (elements 0)))
(cond ((symbol? el0)
eq?)
((number? el0)
=)
((string? el0)
string=?)
((pair? el0)
equal?)
(else
morally-equal?))))))
eq-func)
(define (get-vector)
(when (not vector*)
(if (vector? elements)
(set! vector* elements)
(set! vector* (to-vector (get-list)))))
vector*)
(define (get-list)
(when (not list*)
(if (hash-table? elements)
(set! list* (map car elements))
(set! list* (to-list elements))))
list*)
(define (get-hash)
(when (not hash)
;;(c-display "================ elements:" elements ". num:" (get-size) "====================")
(set! hash (make-hash-table (i-max 1 (get-size)) (get-eq-func)))
(for-each (lambda (element)
(set! (hash element) #t))
elements))
hash)
(define (get-size)
(when (not num-elements)
(if hash
(set! num-elements (hash-table-entries hash))
(set! num-elements (vector-length (get-vector)))))
num-elements)
:contains (key)
((get-hash) key)
:intersection (elements2)
(keep (lambda (el2)
(this->contains el2))
elements2)
:set-difference (elements2) ;; returns all elements in 'elements2' that are not in 'this'.
(let ((elements2 (if (pair? elements2)
(<new> :container elements2)
elements2)))
(if (hash-table? (elements2 :elements))
(let ((ret (copy (elements2 :elements))))
(this->for-each (lambda (el2)
(hash-table-set! ret (car el2) #f)))
(<new> :container ret))
(<new> :container (remove (lambda (el2)
(if (pair? el2)
(this->contains (car el2))
(this->contains el2)))
(elements2 :elements)))))
:has-all? (elements2)
(every? (lambda (el2)
(this->contains el2))
elements2)
:for-each (func)
(cond (list*
(for-each func list*))
(vector*
(for-each func vector*))
(else
(for-each (lambda (el)
(func (car el)))
hash)))
:num-elements ()
(get-size)
:size ()
(get-size)
:length ()
(get-size)
:vector ()
(get-vector)
:list ()
(get-list)
:hash ()
(get-hash)
:elements ()
elements
:get (pos)
((get-vector) pos)
:remove! (element)
(let ((eq-func (get-eq-func)))
(let loop ((elements (get-list))
(new-elements '())
(num-removed 0))
(cond ((null? elements)
(let ((new-elements (reverse! new-elements)))
(clear! new-elements
#f
new-elements
#f
#f)
num-removed))
((eq-func (car elements) element)
(loop (cdr elements)
new-elements
(+ 1 num-removed)))
(else
(loop (cdr elements)
(cons (car elements) new-elements)
num-removed)))))
:add! (element) ;; Very inefficient if primary format is hash-table.
(let ((elements (cons element (get-list))))
(clear! elements
#f
elements
#f
(and num-elements
(+ 1 num-elements))))
:add-unique! (element) ;; Very inefficient if primary format is not hash-table.
(when (not (this->contains element))
(set! (hash element) #t)
(clear! hash
#f
(and list*
(cons element list*))
hash
(and num-elements
(+ 1 num-elements))))
:cons (element)
(<new> :container (cons element (get-list))))
#||
=>
(delafina (new_instance_of_list-and-set :alist
:eq-func eq?)
(define hash (make-hash-table (max 1 (length alist)) eq-func))
(for-each (lambda (element)
(set! (hash element) #t))
alist)
(define (this->contains key)
(hash key))
(define (this->list)
alist)
(define (this->set)
hash)
(define methods_of_list-and-set
(hash-table :contains this->contains
:list this->list
:set this->set))
(lambda (methodname . rest)
(let ((func (methods_of_list-and-set methodname)))
(if func
(apply func rest)
(error (<-> "Method \"" methodname "\" not found in class list-and-set"))))))
||#
(define-constant *num-radium-ticks* (<ra> :get-highest-legal-place-denominator))
(define-constant *smallest-radium-tick* (/ 1 *num-radium-ticks*))
(define (-line linenum)
(- linenum *smallest-radium-tick*))
#||
(define (+line linenum)
(+ linenum *smallest-radium-tick*))
||#
(define (undo-block block)
(<ra> :open-undo)
(try-finally :try block
:finally (lambda ()
(<ra> :close-undo))))
(define (ignore-undo-block block)
(<ra> :start-ignoring-undo)
(try-finally :try block
:finally (lambda ()
(<ra> :stop-ignoring-undo))))
;; ensures that (<ra> :update-notes-in-player) is only called after the outermost block is finished.
(define *currently-in-update-notes-after-block-block* #f)
(define (update-notes-after-block block)
(if *currently-in-update-notes-after-block-block*
(block)
(begin
(set! *currently-in-update-notes-after-block-block* #t)
(try-finally :try block
:finally (lambda ()
(set! *currently-in-update-notes-after-block-block* #f)
(<ra> :update-notes-in-player))))))
(define (draw-plot xs func)
(define ys (map func xs))
(define args "")
(for-each (lambda (x y)
(set! args (<-> args " " (* 1.0 x) " " (* 1.0 y) )))
xs ys)
(system (<-> "plot" args "&"))
;;(read-char)
(c-display "args" args)
ys)
#||
(define (fibgakk arg)
(if (= arg 0)
(<ra> :testsomething arg)
(fibgakk (1- arg))))
(define (test-crash)
(fibgakk 50))
||#
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
;; Coroutines (missing yield and so forth, but we don't need it it, at least not yet)
;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;
(define-struct coroutine
:func #f
:is-scheduled #f
:is-running #f
:please-stop-me #f)
(define (coroutine-alive? coroutine)
;;(c-display "coroutine:" coroutine (coroutine :is-scheduled) (coroutine :is-running))
(or (coroutine :is-scheduled)
(coroutine :is-running)))
(define (stop-coroutine! coroutine)
(cond ((coroutine :is-scheduled)
(let ((func (coroutine :func)))
(<ra> :remove-schedule func)
(set! (coroutine :is-scheduled) #f)))
((coroutine :is-running)
(set! (coroutine :please-stop-me) #t))
(else
#f)))
(define (run-coroutine coroutine args func)
(define (coroutine-helper)
(set! (coroutine :is-scheduled) #f)
(when (not (coroutine :please-stop-me))
(let loop ((args args))
(set! (coroutine :is-running) #t)
(let ((pausetime-and-args (eat-errors :try (lambda ()
(apply func args))
:failure-return-value #f)))
(set! (coroutine :is-running) #f)
(if (and (not (coroutine :please-stop-me))
pausetime-and-args)
(let* ((pausetime (car pausetime-and-args))
(next-args (cdr pausetime-and-args)))
(if (> pausetime 0)
(schedule-next! next-args pausetime)
(loop next-args)))))))
#f)
(define (schedule-next! next-args pausetime)
(set! args next-args)
(set! (coroutine :is-scheduled) #t)
(<ra> :schedule pausetime coroutine-helper))
(assert (not (coroutine-alive? coroutine)))
(set! (coroutine :please-stop-me) #f)
(set! (coroutine :func) coroutine-helper) ;; Not currently used for anything.
(schedule-next! args 0))
(let ()
(<declare-variable> notdefined)
(***assert-error*** (+ notdefined) 'unbound-variable))
|
Extinction Rebellion: NHS reports patient to counter-extremism programme for joining non-violent environmental group The 69-year-old man was shocked to find police at his door over support for the green group
A retired doctor asking for protest-related health advice to embark on an Extinction Rebellion demonstration was reported to the government’s counter-terrorism programme by his GP.
Lyn Jenkins, 69, reportedly consulted his doctor for advice to overcome his fear of claustrophobia.
The man feared he would suffer from panic attacks if he was arrested and detained in a cell as a part of the environmental campaign group, The Guardian reported.
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But following the appointment, Dr Jenkins was surprised to find two police officers at his door after his local NHS trust had reported him to counter-terrorist programme Prevent, because he said he would willingly be arrested for the cause.
Extinction Rebellion member visited by police
Extinction Rebellion believes members of its campaign should get arrested for the cause to raise awareness surrounding the climate crisis.
The peaceful protest group had 1000 of its activists arrested by April 2019, with the Metropolitan Police pushing for more than 1,100 people to be charged over Extinction Rebellion protests in London.
Supportive of the protest group’s mantra, Dr Jenkins reportedly told his GP he would be willing to get arrested to further the cause during the appointment.
It was this statement that led the health professional to report him to Prevent, a programme designed to stop individuals from getting involved or supporting terrorism.
Although the officers took no further action after checking in on the retired doctor’s wellbeing, the retiree told The Guardian the NHS’ action caused him concern.
He said: “Extinction Rebellion is, above all, a non-violent movement. Labelling peaceful protesters as terrorists leaves them, and the world as a whole, in a more perilous position.”
What is Prevent? Prevent is a government programme launched to stop vulnerable people from entering terrorist circles. Launched in 2006 by the Home Office, the counter-extremism programme has been mired in controversy because of the methods used to report those considered to be susceptible to extremist organisations. Some critics have questioned to what extent the programme prevents terrorist attacks. Manchester suicide bomber Salman Abedi was reported to the programme five times before he carried out the Manchester arena bombing in 2017.
‘Vulnerable to exploitation’
Oxford Health NHS Foundation Trust defended the move, stating it has a responsibility to “protect people who may be vulnerable to exploitation.”
It said the medical professional was well within their rights to report Mr Jenkins after he declared his intention to be arrested while participating in protests.
The trust said in a statement: “We have a responsibility to fulfil our safeguarding obligations to protect people who may be vulnerable to exploitation.
“There is a range of safeguarding matters on which we may seek advice, depending on the issue, whether that’s child protection, domestic abuse or radicalisation.
“Prevent is part of the safeguarding programme, with a remit that extends beyond terrorist activity.
“If someone seeks treatment with us with the declared intention of enabling themselves to be arrested, that would prompt us to consider whether they were vulnerable or were being exploited by following the appropriate safeguarding process.”
Confidential patient details
NHS bosses have been told by the head of the Health Committee to stop handing over confidential patient information to the Home Office, which uses the data as part of efforts to locate suspected illegal migrants.
Dr Sarah Wollaston said the practice, which has risen threefold in the last three years, is “deeply concerning” and showed an “unacceptable disregard for serious unintended consequences”.
The Conservative MP said: “It is essential that all patients can trust that their confidential personal information, including their address, will not be shared without consent. Only in exceptional circumstances should that principle be breached & after full consideration of the public interest. [It] really was not for NHS Digital to in effect rewrite the principles underpinning confidentiality.”
i has contacted Extinction Rebellion and the Home Office for comment. |
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